Studying The Role of Alpha-Synuclein in Huntington's Disease
Huntington’s disease (HD) is a type of neurodegenerative disorder in which progressive degeneration of medium spiny neurons in the striatum, a portion of the basal ganglia with connections to systems that govern motor control and emotional regulation. Degeneration is caused by a trinucleotide CAG repeat expansion in the gene encoding huntingtin protein (HTT) which causes polyglutamine repeat expansions during protein translation. HTT then forms aggregates that interrupt normal cellular function and homeostasis. Alpha-synuclein (α-syn), a cytoplasmic protein (encoded by SNCA) involved in function and maintenance of synapses whose dysfunction has been robustly linked to Parkinson’s disease (PD), has recently been demonstrated to have a modulatory role in HD pathogenesis and progression. By interacting with protein kinase 2α-prime (CK2α’), α-syn encourages the degradation of heat shock factor 1 (HSF1), an important regulator of the transcription of heat shock proteins (HSPs), a major proteostatic mechanism in the cell. HSF1 degradation leads to increased protein aggregation and neuronal death. CK2α’ also encourages phosphorylation of α-syn on serine residue 129, which is the predominant form of α-syn observed to be present in protein aggregates in HD. Though it has been determined that α-syn plays a role in early stages of HD pathogenesis due to its effects on phenotype and expression of HSPs, the mechanism by which α-syn affects the cellular machinery to encourage neuronal dysregulation remains unclear. Here we show that despite transcriptional repression of SNCA in HD model cells, α-syn presence is significantly increased in wild-type (WT) cells. However, α-syn was observed to have lowered nuclear colocalization in HD model cells. Notwithstanding, overexpression of α-syn in WT cells lead to suppression of Slc17a7, the gene encoding VGLUT1, an important glutamate transporter in the brain. Taken in conjunction, these findings suggest that α-syn colocalization to the nucleus may be more closely related to its phosphorylation state and that unphosphorylated α-syn may be capable of influencing proteins at the translational or post-translational level when elevated. This study represents an important next step in the search for viable therapeutic targets in the treatment of HD by providing evidence of altered expression of important neural transporters.