GBA1-Associated Parkinson's Disease Is a Distinct Entity

Abstract

GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

Keywords: GBA1 variants; GBA1-associated Parkinson disease; Parkinson’s disease; clinical presentation and course; genotype-phenotype correlations; pathophysiology and molecular mechanisms; treatment options.

Figure 1

GBA1 ‘Gain-of-function’ scenario for alpha-synuclein aggregation. (A) In healthy individuals, glucocerebrosidase (GCase) is synthesized in the endoplasmic reticulum (ER), properly folded, then trafficked to the Golgi apparatus (GA) for processing, and subsequently transported to the lysosome, where it degrades Glucosylceramide (GlcCer) to glucose (Glc) and ceramide (Cer). GCase is itself degraded in the lysosome by lysosomal enzymes. Cytoplasmic alpha-synuclein (AS) is degraded via two primary pathways: the ubiquitin–proteasome system (UPS) in the cytoplasm and the autophagy-lysosomal pathway (ALP) in the lysosome. (B) In GBA1-associated Parkinson’s disease (PD), mutant/misfolded GCase (mGCase) is recognized as misfolded in the ER, initiating ER stress and activation of the Unfolded Protein Response (UPR); mGCase is retained ER for further attempts to refold. When not successful, it undergoes retrotranslocation. Normal GCase (GCase) reaches the lysosome effectively and facilitates the degradation of GlcCer into Glc and Cer, and then itself is degraded in the lysosome by lysosomal enzymes. mGCase is directed to the UPS and ALP for degradation. Concurrently, the overburdening of the UPS and ALP due to the mGCase prevents AS from degrading at a normal pace, leading to its aggregation and the formation of Lewy bodies.