SCA1-like Disease in Mice Expressing Wild-Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776

Bagley

Proc. Natl. Acad. Sci. U.S.A.

et al. 2011

Whereas the neurodegeneration associated with various polyglutamine (polyQ) diseases has prompted extensive studies of polyQ-induced cell death, the neuronal loss that typically appears during late stages of the diseases may not account for the preceding movement and mental disorders. The cellular basis for polyQ-induced neuronal dysfunction preceding neuronal cell death remains largely unknown. Here we report defective dendrite morphogenesis within a specific subset of neurons due to polyQ toxicity that can be dissociated from caspase-dependent cell death. Expressing pathogenic spinocerebellar ataxia type 1 (SCA1) or type 3 (SCA3) proteins in Drosophila larval dendritic arborization neurons caused neuronal type-specific dendrite phenotypes primarily affecting terminal branches. We further show that expression of pathogenic polyQ proteins in adult flies after the formation of neuronal dendrites also greatly reduced dendritic complexity. These defects are associated with disruption of dendritic F-actin structures that can be partially mitigated by increasing Rac-PAK signaling. Together, these findings suggest that specific actin cytoskeletal alterations that alter dendrite morphology and function may contribute to the pathogenesis of at least a subset of polyQ disorders, including SCA3 and SCA1.

Section: Resultsmentioning

confidence: 99%

Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila

Bagley

Proc. Natl. Acad. Sci. U.S.A.

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

“…The protocols for protein extraction and gel filtration chromatography have been described (17). The antibodies used for protein blotting were commercially available or are described elsewhere (17): rabbit polyclonal antibody to 14-3-3ε (Cell Signaling), guinea pig polyclonal antiserum to Capicua (CIC) (17), mouse monoclonal antibody to Flag M2 (Sigma), rabbit polyclonal antibody to ATXN1 (11750-VII) (17), mouse monoclonal anti-ATXN1 antibody, rabbit polyclonal antibody to pATXN1 (37), and mouse monoclonal antibody to GAPDH (Advanced ImmunoChemical). Anti-FLAG M2 affinity gel freezer-safe (A2220; Sigma) was used for immunoprecipitation after column fractionation.…”

Section: Methodsmentioning

confidence: 99%

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3 ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration

Jafar‐Nejad¹,

Ward²,

Richman

et al. 2011

Self Cite

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1 154Q/+ mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.

“…At this stage, there are also abnormalities in the structure of climbing fiber synaptic contacts, namely a loss of synapses in the distal dendritic tree and persistence of climbing fiber contacts on the soma that are normally pruned during development [30]. With disease progression, Purkinje neurons continue to show reduced responsiveness at climbing fiber synapses and a reduction in the volume of climbing fiber afferents onto Purkinje neurons [31]. All of these data, taken together, suggest that in SCA1 there is reduced Purkinje neuron responsiveness to both climbing fiber and parallel fiber synapses.…”

Section: Sca1mentioning

confidence: 99%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.