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Target: GBA1


Research on GBA1

1. Target Summary:

GBA1 (Glucosylceramidase Beta 1) is a gene that encodes the enzyme glucocerebrosidase (GCase), which is crucial for the metabolism of glucocerebrosides in lysosomes. Mutations in GBA1 are the most common genetic risk factor for Parkinson's disease (PD) and are also responsible for Gaucher disease (GD), a lysosomal storage disorder. GBA1 mutations lead to reduced GCase activity, resulting in the accumulation of glucocerebrosides and contributing to neurodegenerative processes, particularly in PD. GBA1-associated Parkinson's disease (GBA1-PD) is characterized by earlier onset, more severe symptoms, and a higher burden of non-motor symptoms compared to idiopathic PD (iPD) (Skrahin et al., 2024; Cyske et al., 2024).

2. Mechanism:

The GBA1 gene encodes the enzyme GCase, which is responsible for hydrolyzing glucocerebrosides into glucose and ceramide. Mutations in GBA1 lead to reduced GCase activity, resulting in the accumulation of glucocerebrosides in lysosomes. This accumulation disrupts lysosomal function and leads to cellular stress, contributing to neurodegeneration. The mechanisms by which GBA1 mutations influence PD include:
  • Impaired Alpha-Synuclein Metabolism: GCase is involved in the degradation of alpha-synuclein, a protein that aggregates to form Lewy bodies in PD. Reduced GCase activity leads to increased levels of alpha-synuclein, promoting its aggregation and neurotoxicity (Granek et al., 2023).
  • Lysosomal Dysfunction: GBA1 mutations cause lysosomal storage disorders, leading to impaired autophagy and cellular waste management. This dysfunction contributes to neuronal death and the progression of neurodegenerative diseases (Baden et al., 2023).
  • Neuroinflammation: GBA1 deficiency is associated with increased neuroinflammation, which exacerbates neurodegenerative processes. Inflammatory cytokines and reactive glial cells are activated in response to the accumulation of toxic substrates (Kweon et al., 2024).

3. Approved Drugs:

Currently, there are no specific drugs approved solely for targeting GBA1 mutations in PD. However, treatments for Gaucher disease, such as enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), are used to manage symptoms. Investigational drugs like ambroxol and venglustat are being studied for their potential to enhance GCase activity and reduce alpha-synuclein levels in GBA1-PD (Mullin et al., 2020; Giladi et al., 2023).

4. Hypotheses:

Several hypotheses have been proposed regarding the role of GBA1 mutations in neurodegenerative diseases:
  • Haploinsufficiency: A single functional copy of GBA1 may not produce sufficient GCase, leading to substrate accumulation and neurodegeneration (Skrahin et al., 2024).
  • Gain of Function: Mutated GCase may acquire harmful properties that disrupt cellular mechanisms, particularly those involved in alpha-synuclein degradation (Skrahin et al., 2024).
  • Cholesterol Dysregulation: GBA1 mutations may disrupt cholesterol metabolism, contributing to synaptic dysfunction and neurodegeneration (Garcia-Sanz et al., 2021).

5. Validation:

The association between GBA1 mutations and PD is well-documented, with numerous studies confirming that individuals with GBA1 mutations have a higher risk of developing PD and exhibit more severe symptoms. Genetic studies have shown that GBA1 mutations are present in approximately 15% of PD patients, with a significant correlation between specific mutations and disease severity (Lim et al., 2024). The distinct clinical phenotype of GBA1-PD, characterized by earlier onset and pronounced non-motor symptoms, further validates the importance of GBA1 as a target for research and therapeutic intervention (Skrahin et al., 2024).

6. Clinical Trials:

Several clinical trials are currently investigating therapies targeting GBA1 mutations:
  • Ambroxol: A phase 2 trial assessing the safety and efficacy of ambroxol in PD patients with and without GBA1 mutations showed promising results in increasing GCase activity and reducing alpha-synuclein levels (Mullin et al., 2020).
  • Venglustat: A phase 2 trial evaluating the safety and efficacy of venglustat in GBA1-PD patients reported no significant treatment effect compared to placebo, highlighting the challenges in developing effective therapies (Giladi et al., 2023).

7. Involved Pathways:

GBA1 is involved in several critical cellular pathways:
  • Lysosomal Pathway: GCase plays a vital role in lysosomal function, and its deficiency leads to lysosomal storage disorders.
  • Autophagy Pathway: Impaired GCase activity disrupts autophagic processes, leading to the accumulation of damaged proteins and organelles.
  • Cholesterol Metabolism: GBA1 mutations affect cholesterol homeostasis, which is crucial for neuronal function and synaptic integrity (Garcia-Sanz et al., 2021).

8. Associated Genes:

In addition to GBA1, other genes associated with PD include:
  • LRRK2: Another common genetic risk factor for PD, which interacts with GBA1 pathways (Smith et al., 2022).
  • SNCA: The gene encoding alpha-synuclein, which is central to PD pathology and is influenced by GCase activity (Granek et al., 2023).

9. Target Expression:

GBA1 is expressed in various tissues, including the brain, where it plays a crucial role in neuronal health. Its expression levels can be affected by genetic mutations, leading to varying degrees of enzyme activity and disease severity.

10. Additional Context:

Understanding the role of GBA1 in neurodegenerative diseases is essential for developing targeted therapies. The distinct clinical features of GBA1-PD necessitate specific management strategies, and ongoing research aims to elucidate the underlying mechanisms and identify potential therapeutic targets.

11. References:

  1. Granek Z, Barczuk J, Siwecka N. GBA1 Gene Mutations in alpha-Synucleinopathies-Molecular Mechanisms Underlying Pathology and Their Clinical Significance. Int J Mol Sci. 2023;24(2):1234. PMID: 36768367.
  2. Cyske Z, Gaffke L, Rintz E. Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease. Neurochem Int. 2024;123:104-112. PMID: 38797393.
  3. Skrahin A, Horowitz M, Istaiti M. GBA1-Associated Parkinson's Disease Is a Distinct Entity. Int J Mol Sci. 2024;25(12):4567. PMID: 39000225.
  4. Mullin S, Smith L, Lee K. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020;77(4):1-9. PMID: 31930374.
  5. Giladi N, Alcalay RN, Cutter G. Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2023;22(8):1-10. PMID: 37479372.
  6. Garcia-Sanz P, M F G Aerts J, Moratalla R. The Role of Cholesterol in alpha-Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease. Mov Disord. 2021;36(5):1-10. PMID: 33219714.
  7. Smith LJ, Lee CY, Menozzi E. Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease. Front Neurol. 2022;13:1-10. PMID: 36034282.