Huntington’s disease (HD) is caused by CAG / polyglutamine repeat expansions in the huntingtin (htt) gene, yielding proteins that misfold and resist degradation. HD belongs to a large class of neurodegenerative proteinopathies including Alzheimer’s disease, Parkinson’s disease, and tauopathies. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by PPARγ co-activator 1α (PGC-1α), a regulator of mitochondrial biogenesis and oxidative stress. To test if restoration of PGC-1α could treat HD, we attempted an in vivo genetic rescue in mice. We found that PGC-1α induction ameliorates HD neurodegeneration and virtually eliminates htt protein aggregation, in part by attenuating oxidative stress. Further studies revealed that PGC-1α promotes htt turnover and aggregate elimination by transactivation of TFEB, a master regulator of the autophagy-lysosome pathway, and that TFEB alone is capable of reducing htt aggregation and neurotoxicity, placing PGC-1α upstream of TFEB. PGC-1α and TFEB thus hold great promise as therapies for HD and other neurodegenerative proteinopathies.

Spinocerebellar ataxia type 31 (SCA31) is an adult-onset autosomal-dominant neurodegenerative disorder showing progressive cerebellar ataxia mainly affecting Purkinje cells. The SCA31 critical region was tracked down to a 900 kb interval in chromosome 16q22.1, where the disease shows a strong founder effect. By performing comprehensive Southern blot analysis and BAC- and fosmid-based sequencing, we isolated two genetic changes segregating with SCA31. One was a single-nucleotide change in an intron of the thymidine kinase 2 gene (TK2). However, this did not appear to affect splicing or expression patterns. The other was an insertion, from 2.5-3.8 kb long, consisting of complex penta-nucleotide repeats including a long (TGGAA)n stretch. In controls, shorter (1.5-2.0 kb) insertions lacking (TGGAA)n were found only rarely. The SCA31 repeat insertion's length inversely correlated with patient age of onset, and an expansion was documented in a single family showing anticipation. The repeat insertion was located in introns of TK2 and BEAN (brain expressed, associated with Nedd4) expressed in the brain and formed RNA foci in the nuclei of patients' Purkinje cells. An electrophoretic mobility-shift assay showed that essential splicing factors, serine/arginine-rich splicing factors SFRS1 and SFRS9, bind to (UGGAA)n in vitro. Because (TGGAA)n is a characteristic sequence of paracentromeric heterochromatin, we speculate that the insertion might have originated from heterochromatin. SCA31 is important because it exemplifies human diseases associated with "inserted" microsatellite repeats that can expand through transmission. Our finding suggests that the ectopic microsatellite repeat, when transcribed, might cause a disease involving the essential splicing factors.

Parkinson's disease (PD) is characterized by the accumulation of ␣-synuclein (␣-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing ␣-syn inclusions in PD. Recent data has indicated that loss-offunction mutations in the GBA1 gene that encodes lysosomal ␤-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to ␣-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce ␣-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological ␣-syn, regardless of the disease causing mutations. Importantly, the reduction of ␣-syn was sufficient to reverse downstream cellular pathologies induced by ␣-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce ␣-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies.