Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding protein...
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Autor*in:	Verdile, Veronica [verfasserIn] Palombo, Ramona [verfasserIn] Ferrante, Gabriele [verfasserIn] Ferri, Alberto [verfasserIn] Amadio, Susanna [verfasserIn] Volonté, Cinzia [verfasserIn] Paronetto, Maria Paola [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Alternative splicing Sam68 Amyotrophic lateral sclerosis

Übergeordnetes Werk:	Enthalten in: Progress in neurobiology - Amsterdam [u.a.] : Elsevier, 1973, 231
Übergeordnetes Werk:	volume:231

DOI / URN:	10.1016/j.pneurobio.2023.102529

Katalog-ID:	ELV066119383

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245	1	0	\|a Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
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520			\|a Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.
650		4	\|a Alternative splicing
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650		4	\|a Amyotrophic lateral sclerosis
700	1		\|a Palombo, Ramona \|e verfasserin \|4 aut
700	1		\|a Ferrante, Gabriele \|e verfasserin \|4 aut
700	1		\|a Ferri, Alberto \|e verfasserin \|4 aut
700	1		\|a Amadio, Susanna \|e verfasserin \|4 aut
700	1		\|a Volonté, Cinzia \|e verfasserin \|4 aut
700	1		\|a Paronetto, Maria Paola \|e verfasserin \|0 (orcid)0000-0001-5324-0903 \|4 aut
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publishDate	2023
allfields	10.1016/j.pneurobio.2023.102529 doi (DE-627)ELV066119383 (ELSEVIER)S0301-0082(23)00130-2 DE-627 ger DE-627 rda eng 610 VZ 42.00 bkl 44.90 bkl Verdile, Veronica verfasserin aut Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS. Alternative splicing Sam68 Amyotrophic lateral sclerosis Palombo, Ramona verfasserin aut Ferrante, Gabriele verfasserin aut Ferri, Alberto verfasserin aut Amadio, Susanna verfasserin aut Volonté, Cinzia verfasserin aut Paronetto, Maria Paola verfasserin (orcid)0000-0001-5324-0903 aut Enthalten in Progress in neurobiology Amsterdam [u.a.] : Elsevier, 1973 231 (DE-627)30666142X (DE-600)1500673-6 (DE-576)081986963 1873-5118 nnns volume:231 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 42.00 Biologie: Allgemeines VZ 44.90 Neurologie VZ AR 231
spelling	10.1016/j.pneurobio.2023.102529 doi (DE-627)ELV066119383 (ELSEVIER)S0301-0082(23)00130-2 DE-627 ger DE-627 rda eng 610 VZ 42.00 bkl 44.90 bkl Verdile, Veronica verfasserin aut Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS. Alternative splicing Sam68 Amyotrophic lateral sclerosis Palombo, Ramona verfasserin aut Ferrante, Gabriele verfasserin aut Ferri, Alberto verfasserin aut Amadio, Susanna verfasserin aut Volonté, Cinzia verfasserin aut Paronetto, Maria Paola verfasserin (orcid)0000-0001-5324-0903 aut Enthalten in Progress in neurobiology Amsterdam [u.a.] : Elsevier, 1973 231 (DE-627)30666142X (DE-600)1500673-6 (DE-576)081986963 1873-5118 nnns volume:231 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 42.00 Biologie: Allgemeines VZ 44.90 Neurologie VZ AR 231
allfields_unstemmed	10.1016/j.pneurobio.2023.102529 doi (DE-627)ELV066119383 (ELSEVIER)S0301-0082(23)00130-2 DE-627 ger DE-627 rda eng 610 VZ 42.00 bkl 44.90 bkl Verdile, Veronica verfasserin aut Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS. Alternative splicing Sam68 Amyotrophic lateral sclerosis Palombo, Ramona verfasserin aut Ferrante, Gabriele verfasserin aut Ferri, Alberto verfasserin aut Amadio, Susanna verfasserin aut Volonté, Cinzia verfasserin aut Paronetto, Maria Paola verfasserin (orcid)0000-0001-5324-0903 aut Enthalten in Progress in neurobiology Amsterdam [u.a.] : Elsevier, 1973 231 (DE-627)30666142X (DE-600)1500673-6 (DE-576)081986963 1873-5118 nnns volume:231 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 42.00 Biologie: Allgemeines VZ 44.90 Neurologie VZ AR 231
allfieldsGer	10.1016/j.pneurobio.2023.102529 doi (DE-627)ELV066119383 (ELSEVIER)S0301-0082(23)00130-2 DE-627 ger DE-627 rda eng 610 VZ 42.00 bkl 44.90 bkl Verdile, Veronica verfasserin aut Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS. Alternative splicing Sam68 Amyotrophic lateral sclerosis Palombo, Ramona verfasserin aut Ferrante, Gabriele verfasserin aut Ferri, Alberto verfasserin aut Amadio, Susanna verfasserin aut Volonté, Cinzia verfasserin aut Paronetto, Maria Paola verfasserin (orcid)0000-0001-5324-0903 aut Enthalten in Progress in neurobiology Amsterdam [u.a.] : Elsevier, 1973 231 (DE-627)30666142X (DE-600)1500673-6 (DE-576)081986963 1873-5118 nnns volume:231 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 42.00 Biologie: Allgemeines VZ 44.90 Neurologie VZ AR 231
allfieldsSound	10.1016/j.pneurobio.2023.102529 doi (DE-627)ELV066119383 (ELSEVIER)S0301-0082(23)00130-2 DE-627 ger DE-627 rda eng 610 VZ 42.00 bkl 44.90 bkl Verdile, Veronica verfasserin aut Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS. Alternative splicing Sam68 Amyotrophic lateral sclerosis Palombo, Ramona verfasserin aut Ferrante, Gabriele verfasserin aut Ferri, Alberto verfasserin aut Amadio, Susanna verfasserin aut Volonté, Cinzia verfasserin aut Paronetto, Maria Paola verfasserin (orcid)0000-0001-5324-0903 aut Enthalten in Progress in neurobiology Amsterdam [u.a.] : Elsevier, 1973 231 (DE-627)30666142X (DE-600)1500673-6 (DE-576)081986963 1873-5118 nnns volume:231 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 42.00 Biologie: Allgemeines VZ 44.90 Neurologie VZ AR 231
language	English
source	Enthalten in Progress in neurobiology 231 volume:231
sourceStr	Enthalten in Progress in neurobiology 231 volume:231
format_phy_str_mv	Article
bklname	Biologie: Allgemeines Neurologie
institution	findex.gbv.de
topic_facet	Alternative splicing Sam68 Amyotrophic lateral sclerosis
dewey-raw	610
isfreeaccess_bool	false
container_title	Progress in neurobiology
authorswithroles_txt_mv	Verdile, Veronica @@aut@@ Palombo, Ramona @@aut@@ Ferrante, Gabriele @@aut@@ Ferri, Alberto @@aut@@ Amadio, Susanna @@aut@@ Volonté, Cinzia @@aut@@ Paronetto, Maria Paola @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	30666142X
dewey-sort	3610
id	ELV066119383
language_de	englisch
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author	Verdile, Veronica
spellingShingle	Verdile, Veronica ddc 610 bkl 42.00 bkl 44.90 misc Alternative splicing misc Sam68 misc Amyotrophic lateral sclerosis Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
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topic_title	610 VZ 42.00 bkl 44.90 bkl Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis Alternative splicing Sam68 Amyotrophic lateral sclerosis
topic	ddc 610 bkl 42.00 bkl 44.90 misc Alternative splicing misc Sam68 misc Amyotrophic lateral sclerosis
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title	Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
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title_full	Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
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author_browse	Verdile, Veronica Palombo, Ramona Ferrante, Gabriele Ferri, Alberto Amadio, Susanna Volonté, Cinzia Paronetto, Maria Paola
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title_sort	dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
title_auth	Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
abstract	Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.
abstractGer	Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.
abstract_unstemmed	Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1 G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1 G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.
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title_short	Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis
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author2	Palombo, Ramona Ferrante, Gabriele Ferri, Alberto Amadio, Susanna Volonté, Cinzia Paronetto, Maria Paola
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up_date	2024-07-06T16:38:52.382Z
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Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis

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