Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel

Zhuchenko, Olga; Bailey, Jennifer M.; Bonnen, Penelope E.; Ashizawa, Tetsuo; Stockton, David W.; Amos, Chris; Dobyns, William B.; Subramony, S. H.; Zoghbi, Huda Y.; Lee, Cheng‐Chi

doi:10.1038/ng0197-62

Cited by 1,510 publications

(1,044 citation statements)

References 40 publications

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“…Disorders not associated with FHM are episodic ataxia type 2 (Zafeiriou et al 2009, Cuenca-Leon et al 2009, Cricchi et al 2007, Jen et al 2004, 2008, Ophoff et al 1996, progressive ataxia (Yue et al 1997), spinocerebellar ataxia type 6 (Tsou et al , Restituito et al 2000, Ishikawa et al 1999, Zhuchenko et al 1997) and absence (Imbrici et al 2004) and generalized epilepsy (Haan et al 2005, Jouvenceau et al 2001). In addition FHM1 mutations were also found in family members who had only "normal" no-paretic migraine but no FHM.…”

Section: C2 Familial Hemiplegic Migraine Typementioning

confidence: 99%

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

Uchitel

Inchauspe

Urbano

et al. 2012

Journal of Physiology-Paris

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Section: C2 Familial Hemiplegic Migraine Typementioning

confidence: 99%

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

Uchitel

Inchauspe

Urbano

et al. 2012

Journal of Physiology-Paris

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“…In humans, mutations in the CACNA1A gene cause, in addition to FHM1, a few autosomal dominant neurological disorders characterized by cerebellar dysfunction, such as episodic ataxia type 2 (that may be associated with absence epilepsy in a few cases) and spinocerebellar ataxia type 6 9,26,27 (compare, Strupp 28 and Gomez 29 31,35,37,38 Recently, the generation of knockin mice carrying two different FHM1 mutations (R192Q and S218L) allowed the first analysis of mutant channels expressed at their endogenous level in neurons. [39][40][41] The studies in heterologous expression systems showed that the FHM1 mutations alter many biophysical properties of human Ca V 2.1 channels, in a complex way.…”

Section: Familial Hemiplegic Migraine Type 1 (Fhm1)mentioning

confidence: 99%

Familial Hemiplegic Migraine

2007

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Summary: Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming ␣ 1 subunits of the neuronal voltage-gated Ca 2ϩ channels Ca V 2.1 and Na ϩ channels Na V 1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the ␣ 2 subunit of the Na ϩ , K ϩ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca V 2.1 channel and, as a consequence, increased Ca V 2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the ␣ 2 Na ϩ ,K ϩ -ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na V 1.5 (and presumably Na V 1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K ϩ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K ϩ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.

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“…[1][2][3][4][5][6][7][8][9][10][11] Expansion of polyglutamine repeats is associated with a toxic gain-of-function that affects specific neuronal populations in each of these diseases. 12 Huntington's disease (HD), one of the most extensively studied of these diseases, is a debilitating inherited neurodegenerative disorder characterized by involuntary movements, personality changes, dementia, and early death.…”

Section: Introductionmentioning

confidence: 99%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

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Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel

Cited by 1,510 publications

References 40 publications

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

Familial Hemiplegic Migraine

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

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