IMPORTANCEMutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.OBJECTIVE To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.INTERVENTIONS An escalating dose of oral ambroxol to 1.26 g per day.

Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

α-Synuclein (SNCA) is a substantive component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD). The discovery and subsequent derivation of its role in PD has led to a suprising but fruitful convergence of the fields of biochemistry and molecular genetics. In particular, the manipulation of the cell lines of a number of forms of familial PD has implicated SNCA in distinct and diverse biochemical pathways related to its pathogenesis. This current and rapidly evolving concept indicates PD is a disease in which interacting pathways of oxidative stress, mitochondrial dysfunction and impaired regulation of protein turnover interact to cause dopaminergic cell dysfunction and death. SNCA has a central role in these processes and manipulation of its expression, degradation and aggregation appear to be promising neuroprotective therapeutic targets.Keywords α-Synuclein . Parkinson's disease . Lewy bodies Parkinson's Disease and α-SynucleinPD is a clinical diagnosis characterised by an asymetrical resting tremor, increased tone and bradykinesia. Anosmia, sleep disturbance, constipation and other premotor symptoms may precede this presentation by some years. Cognitive impairment is an early sign of PD and advanced disease is frequently accompanied by a dementia with or without visual hallucinations which overlaps clinically with dementia with Lewy bodies. It has a lifetime risk of 4-5 %, making it the second most common neurodegenerative disease after Alzheimer's disease. Current demographic trends predict a doubling in the number of cases by 2050. It is caused in part by progressive dopaminergic degeneration predominately in the substantia nigra. Traditionally, this was characterized histologically by the presence of Lewy bodies although in recent years a number of familial forms of PD have been identified without them.The characterisation of α-synuclein's (SNCA) role in the pathogenesis of PD began with the discovery of three familial forms of PD associated with mutations in the SNCA gene. Three autosomal dominant mutations which are associated with Lewy body formation-an alanine-to-threonine substitution at position 53 (A53T) with onset of PD in the fifth to sixth decade, an alanine to proline substitution at position 30 (A30P) with onset in the third to fifth decade and a glutamate to lysine substituion at position 46 (E46K) with onset in the fifth to seventh decade-were identified [1][2][3]. The SNCA locus was subsequently shown to be associated with sporadic PD [4][5][6] and SNCA was demonstrated within the Lewy bodies of sporadic PD patients in its fibrillar form [7][8][9]. Transgenic animal models carrying the A30P and A53T mutations have been produced; however, precise replication of the clinical and histological findings of PD patients have been inconsistent. In particular, only A30P and A53T Drosphilia and A53T rats mimic L-DOPA-responsive motor symptoms whilst Lewy body formation does not occur in A30P and A53T Thy1 mice or A53T rats [10] α-Synuclein α-synuclein (SNCA) is a small, hi...

Background: The basis of the pathogenicity of the H50Q variant α-synuclein is unknown.Results: The critical concentration of α-synuclein is decreased by 10-fold by the H50Q mutation, and its aggregation is modulated by the wild-type isoform.Conclusion: Key effects of the H50Q mutation on the aggregation of α-synuclein can be quantified.Significance: Our data provide insights into the mechanism of Lewy body formation in vivo.

ObjectivesGBA1 mutations are a frequent risk factor for Parkinson disease (PD). The aim of this study is to evaluate clinical features in a group of GBA1 mutation–positive individuals over a 6-year follow-up.MethodsThis is a longitudinal study on a cohort of GBA1-positive carriers. We enrolled 31 patients with Gaucher disease type 1 (GD), 29 GBA1 heterozygous carriers (Het GBA group) and 30 controls (HC) at baseline and followed them for 6 years. We assessed baseline motor and non-motor signs of PD in all subjects using clinical questionnaires and scales (reduced Unified Multiple System Atrophy Rating Scale (UMSARS), Montreal Cognitive assessment (MoCA), University of Pennsylvania Smell Identification Test (UPSIT), REM Sleep Behavior Disorder screening questionnaire (RBDsq), Movement Disorders Society Unified Parkinson’s Disease Rating Scale motor subscale (MDS-UPDRS III) and Beck Depression Inventory (BDI). We repeated these at the 6-year follow-up alongside venous blood sampling for measurement of glucocerebrosidase enzymatic activity (GCase). We explored whether the GCase activity level was altered in leucocytes of these subjects and how it was related to development of PD.ResultsWe observed a significant worsening in UMSARS, RBDsq, MDS-UPDRS III and BDI scores at the 6-year follow-up compared with baseline in both the GD and Het GBA groups. Intergroup comparisons showed that GD subjects had significantly worse scores in UPSIT, UMSARS, MoCA and MDS-UPDRS III than HC, while Het GBA displayed worse outcomes in UPSIT and MDS-UPDRS III compared with HC. In GBA1 mutation–positive individuals (Het GBA and GD), an UPSIT score of 23 at baseline was correlated with worse outcome at 6 years in UPSIT, MoCA, MDS-UPDRS III and BDI.ConclusionIn this 6-year-long longitudinal study, GBA1 mutation–positive subjects showed a worsening in motor and non-motor prodromal PD features.

The coming years will require the enhancement of current techniques and the development of new ones to define PD's missing heritability. It will also require functional work to define better and in turn potentially reverse the mechanisms that contribute with large effect sizes to the risk of sporadic PD.

The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.

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