Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons

Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including alpha-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related alpha-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of alpha-synuclein and protect midbrain dopamine neurons from alpha-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype alpha-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant alpha-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of alpha-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T alpha-synuclein into the substantia nigra prevented alpha-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of alpha-synuclein. (C) 2015 The Authors. Published by Elsevier Inc.