Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques.

Diego Sucunza,José L Lanciego,María Collantes,Elvira Roda,José L Labandeira-García,Gloria González-Aseguinolaza,Iván Peñuelas,Ana I Rodríguez-Pérez,Alfonso Vázquez,Alberto J Rico,Vania Broccoli

doi:10.3390/ijms22094825

Abstract

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.

Highlights

The GBA1 gene is located in chromosome 1 of the human genome and encodes the lysosomal enzyme glucocerebrosidase (GCase) that hydrolyzes glucosylceramide down to glucose and ceramide
By taking advantage of two animal models of rAAV-induced α-syn aggregation, the conducted approach revealed that using rAAV9-GBA1 resulted in a substantial clearance of α-syn aggregates, further leading to dopaminergic cell neuroprotection
Neurotoxin-based mammalian animal models of Parkinson’s disease (PD) have settled the basis for most of our current understanding of basal ganglia function and dysfunction [20,21], these models failed to recapitulate the main neuropathological hallmarks that typically characterize PD

Summary

Introduction

The GBA1 gene is located in chromosome 1 of the human genome and encodes the lysosomal enzyme glucocerebrosidase (GCase) that hydrolyzes glucosylceramide down to glucose and ceramide. GBA1 mutations [2,5], these patients facing a slight earlier disease onset together with a more aggressive disease course, including a faster progression to dementia, a higher prevalence of neuropsychiatric symptoms, autonomic dysfunction and increased risk of mortality [6]. It is worth noting that up to 1% of individuals in the general population are heterozygous GBA1 mutation carriers [7], this incidence increasing to 6% in the Ashkenazi Jewish population [8]. It has been postulated a relationship between the type of GBA1 mutation variant and the risk of PD and dementia. The N370S mutation variant (currently known as p.Asn409Ser) seems to be closer to PD, whereas the L444P mutation (renamed as p.Leu483Pro) is more likely associated with a faster progression to dementia [9]

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Methods

Conclusion