Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from tran...

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SP...

The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different...

Autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Nearly 33 genetically distinct subtypes have been defined, and 19 seemingly unrelated disease genes have been identified so far. Recently, mutations in the ATPase family gene 3-like 2 (AFG3L2) gene were presented to cause SCA28 sub...

Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP) analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*), establishing the diagnosis of autosomal recessi...

Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na(+) (NaV) 'resurgent' current, which allows renewed Na(+) influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent current have not been fully identified...

The cerebellum is a brain structure involved in coordination, control, and learning of movements, as well as certain aspects of cognitive function. Purkinje cells are the sole output neurons from the cerebellar cortex and therefore play crucial roles in the overall function of the cerebellum. The type-1 metabotropic glutamate receptor (mGluR1) is a key "hub" molecule that is critically involved...

Mutations disrupting primary cilia cause retinal, renal, and cerebellar defects, and misregulated Sonic hedgehog signaling. A new mouse mutant in the TTBK2 kinase fails to make cilia, and shows neural tube and Sonic hedgehog signaling defects. Ciliary targeting mutations in human TTBK2 are linked to spinocerebellar ataxia, suggesting cilia protect from neurodegeneration.

Coenzyme Q10 (CoQ10) is critical for the cell power supply in mitochondria. CoQ10 shuttles electrons from complexes I and II to complex III, and can be anti-oxdiative. Neurons require high energy for synaptic transmission and therefore the mitochondria dysfunction often leads to severe neuronal degeneration, as observed in many neurological disorders. CoQ10 supplementation has been widely used ...