Upregulating \u03b2-hexosaminidase activity in rodents prevents \u03b1-synuclein lipid associations and protects dopaminergic neurons from \u03b1-synuclein-mediated neurotoxicity

Oeystein R Brekk,Zachary K Macbain,Penelope J Hallett,Mylene Huebecker,Frances M Platt,Sara Ann Rosenthal,Cecile C Crapart,Ole Isacson,Joanna A Korecka,Miguel Sena-Esteves,David A Priestman

doi:10.1186/s40478-020-01004-6

Abstract

Sandhoff disease (SD) is a lysosomal storage disease, caused by loss of β-hexosaminidase (HEX) activity resulting in the accumulation of ganglioside GM2. There are shared features between SD and Parkinson’s disease (PD). α-synuclein (aSYN) inclusions, the diagnostic hallmark sign of PD, are frequently found in the brain in SD patients and HEX knockout mice, and HEX activity is reduced in the substantia nigra in PD. In this study, we biochemically demonstrate that HEX deficiency in mice causes formation of high-molecular weight (HMW) aSYN and ubiquitin in the brain. As expected from HEX enzymatic function requirements, overexpression in vivo of HEXA and B combined, but not either of the subunits expressed alone, increased HEX activity as evidenced by histochemical assays. Biochemically, such HEX gene expression resulted in increased conversion of GM2 to its breakdown product GM3. In a neurodegenerative model of overexpression of aSYN in rats, increasing HEX activity by AAV6 gene transfer in the substantia nigra reduced aSYN embedding in lipid compartments and rescued dopaminergic neurons from degeneration. Overall, these data are consistent with a paradigm shift where lipid abnormalities are central to or preceding protein changes typically associated with PD.

Highlights

Age-related neurodegenerative diseases, such as Parkinson’s disease (PD), have many etiological roots that converge on mitochondrial, lipid, protein and inflammatory pathological mechanisms [16, 19]
Physiological associated protein α-synuclein (aSYN) strongly binds gangliosides [11, 25, 47], but previous studies in aSYN-ganglioside protein-lipid interactions have arrived at opposing conclusions regarding the outcomes of this interaction
A previous in vitro study reported binding by all a-series gangliosides including GM1, GM2, and GM3 – to inhibit aSYN fibril formation [27], while a more recent in vitro report on the contrary found GM1 and GM3 to be potent accelerators of aSYN aggregation [13]

Summary

Introduction

Age-related neurodegenerative diseases, such as Parkinson’s disease (PD), have many etiological roots that converge on mitochondrial, lipid, protein and inflammatory pathological mechanisms [16, 19]. Brekk et al Acta Neuropathologica Communications (2020) 8:127 which locus is mutated: Tay-Sachs disease (HEXA) and Sandhoff disease (SD) (HEXB) [6] In both cases, the net effect is loss of the HEX A + B heterodimer, and both diseases are characterized by neuronal swelling and degeneration caused by elevated ganglioside storage [41]. Genome-wide association studies have identified PD risk variants in three additional lysosomal genes (GUSB, GRN, and NEU1) [56], and cell-type specific enrichment of lysosomal genes have demonstrated associations to PD heritability when selecting for astrocytic, microglial and oligodendroglial subtypes [36] Enzymatic activity of both GCase and HEX are progressively lost with age in PD [17, 38], with HEX-activity only showing significant downregulation compared to healthy subject controls in patients aged 80 years or older [17, 28]. We found that upregulated HEX activity rescued degeneration of rat dopaminergic neurons and limited interactions between lipid compartments and overexpressed aSYN

Methods

Findings

Discussion