Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies

Abstract

Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate α-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (Gba1 D409V/D409V) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic Gba1 D409V/D409V mice and in a transgenic mouse model overexpressing A53T α-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic Gba1 D409V/D409V mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant α-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1 D409V/D409V mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T α-synuclein mice reduced the levels of soluble α-synuclein, suggesting that increasing the glycosidase activity can modulate α-synuclein processing and may modulate the progression of α-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1-related and non-GBA1-associated synucleinopathies, including PD.lysosomal storage diseases | mouse models | MAPT | memory defect M utations in the gene for glucocerebrosidase (GBA1) present the highest genetic risk factor for developing synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB) (1-5). The central nervous system (CNS) of Gaucher patients and carriers who present with parkinsonism and dementia harbor deposits of α-synuclein-positive Lewy bodies (LBs) and Lewy neurites (LNs) in hippocampal neurons and their processes resembling those noted in patients with classical PD and DLB (6, 7). Aspects of these characteristics have also been noted in the CNS of several mouse models of neuropathic and nonneuropathic Gaucher disease (8-10). Consequently, a causal relationship has been suggested between the loss of glucocerebrosidase activity or the lysosomal accumulation of undegraded metabolites and the development of PD and DLB. A more direct link between glucocerebrosidase activity and α-synuclein metabolism has been highlighted by studies of Gaucher cells and mice indicating that a reduction in glucocerebrosidase activity by pharmacological or genetic interventions resulted in increased levels of α-synuclein aggregates (9-12). Moreover, a decrease in glucoce...

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

“…Mutations in GBA are now recognized as an independent risk factor for development of cognitive impairment in patients with PD (24)(25)(26)(27). The Gba D409V/D409V mice present several distinct features of synucleinopathies, including cognitive impairment and pathogenic accumulation of α-synuclein, ubiquitin, and tau aggregates (21,22). The assessment of memory function in Gba D409V/D409V mice treated with GZ667161 for 2 mo with the novel object recognition test revealed a modest but significant improvement in memory function (cohort 1, Fig.…”

“…The leading hypothesis posits that GBA-mediated loss of function would cause an abnormal glycosphingolipid environment leading to cellular protein mishandling (proteinopathy) and neuronal dysfunction (16). A decrease in glucocerebrosidase activity is thought to induce an increase in CNS α-synuclein/ubiquitin/tau aggregates and to exacerbate behavioral deficits (13,(16)(17)(18)(19)(20)(21)(22). These pathological and behavioral aberrations can be ameliorated by virus-mediated overexpression of exogenous glucocerebrosidase in the CNS, which might act by restoring membrane glycosphingolipids (16,(21)(22)(23).…”

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

“…It has been shown in SH‐SY5Y cell cultures, neuronal cultures, conduritol‐β‐epoxide (CβE)‐treated mice, and transgenic Gba1 mouse models that reduced GCase activity results in increased α‐synuclein levels 7, 8, 9, 10, 11, 12, 13, 14. Conversely, it has been demonstrated in cell models that increased α‐synuclein causes a decrease in GCase activity 15.…”

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

“…Specifically, lysosomalautophagic dysfunction, defects in ERAD, and alterations in membrane lipid composition have been proposed as mechanisms by which GBA1 mutations cause LBDs and α -synuclein accumulation. Adeno-associated virus (AAV)-mediated expression of GCase reversed the abnormal accumulation of glucosylsphingosine and reduced the levels of proteinase K-resistant α -synuclein in symptomatic GBA1 (D409V/D409V) mice (Sardi et al , 2013 ). Furthermore, overexpression of GCase in A53T α -synuclein mice reduced the levels of soluble α -synuclein.…”