Gba N370S is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
The N370S (also known as N409S) variant in the GBA (Glucosylceramidase, Beta) gene is the most common pathogenic mutation associated with Parkinson's disease, particularly in individuals of Ashkenazi Jewish ancestry.
| Property |
Value |
| Gene |
GBA |
| Nucleotide Change |
c.1226A>G |
| Protein Change |
p.N370S |
| Chromosomal Location |
1q21 |
| Inheritance |
Autosomal Recessive (carrier risk) |
| Penetrance |
~10-30% by age 80 for carriers |
| Population |
Carrier Frequency |
% of PD Cases |
| Ashkenazi Jewish |
5-10% |
15-25% |
| Non-Jewish European |
0.5-1% |
3-5% |
| African |
Very rare |
<1% |
| East Asian |
Very rare |
<1% |
GBA encodes glucosylceramidase (also called glucocerebrosidase or GCase):
- Lysosomal enzyme that hydrolyzes glucosylceramide to glucose + ceramide
- Critical for glycosphingolipid metabolism
- Located in lysosome lumen (requires GBA2 for ER function)
- N370S reduces enzyme activity by ~50-80%
- Impaired glucosylceramide hydrolysis
- Accumulation of glucosylceramide in lysosomes
- GCase deficiency increases alpha-synuclein aggregation
- Glucosylceramide stabilizes toxic alpha-synuclein oligomers
- Bidirectional: alpha-synuclein inhibits GCase
- Impaired autophagic flux
- Mitochondrial dysfunction
- Endoplasmic reticulum stress
- Microglial activation
- Increased cytokine production
- Enhanced neuroinflammation
- Age of onset: 55-65 years (earlier than idiopathic PD)
- Motor symptoms: Typical PD phenotype
- Non-motor symptoms: More prominent
- Disease progression: May be faster
| Feature |
GBA-PD |
Idiopathic PD |
| Cognitive impairment |
40-50% |
20-30% |
| Dementia |
More common, earlier |
Variable |
| Autonomic dysfunction |
60% |
40% |
| Depression |
30% |
25% |
| Anosmia |
70% |
80% |
| REM sleep behavior disorder |
30% |
25% |
- Severe: Early-onset, rapid progression, dementia
- Moderate: Typical onset, standard progression
- Mild: Late-onset, slow progression
| Approach |
Agent |
Stage |
Notes |
| Enzyme enhancement |
Ambroxol |
Phase 2/3 |
Increases GCase activity |
| Substrate reduction |
Eliglustat |
Approved for Gaucher |
May help PD |
| Gene therapy |
AAV-GBA |
Preclinical |
Restores GCase |
| Chaperone therapy |
Small molecules |
Preclinical |
Stabilize mutant GCase |
Ambroxol is a GCase enhancer that has shown promise:
| Study |
Phase |
Participants |
Outcome |
| NCT02941866 |
Phase 2 |
20 GBA-PD |
Safe, CSF GCase increased |
| NCT04588285 |
Phase 3 |
400 GBA-PD |
Ongoing |
| AMPLE |
Phase 2 |
75 GBA-PD |
Cognitive benefit? |
- Motor: MDS-UPDRS
- Cognitive: MoCA, RBANS
- Biomarkers: Alpha-synuclein in CSF, glucosylceramide
| Model |
Phenotype |
Notes |
| GBA KO mouse |
Alpha-synuclein accumulation |
Lethal if complete KO |
| GBA D409V knockin |
PD-like phenotype |
Progressive model |
| GBA/+ heterozygous |
Mild phenotype |
Carrier model |
- Indications: PD patients of Ashkenazi Jewish descent, early cognitive impairment
- Method: Targeted testing for N370S or full GBA sequencing
- Other GBA mutations: L444P, E326K, RecNciI
- Elevated glucosylceramide in blood
- Reduced GCase activity in PBMCs
- Alpha-synuclein seeding assay positive
- 50% chance of passing variant to children
- Increased PD risk (not deterministic)
- Consider genetic counseling
- Family members may benefit from testing
- Ashkenazi Jewish partner testing important
- Reproductive implications
The study of Gba N370S has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Sidransky E, et al. Multicenter analysis of glucocerebosidase mutations in Parkinson disease. N Engl J Med. 2009;361(17):1651-1661. PMID:19846850
- Mazzulli JR, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146(1):37-52. PMID:21700325
- Liu G, et al. GBA deficiency in practice: A review of the current state. Mov Disord. 2022;37(5):917-928. PMID:35146732
- Sardi SP, et al. Glucosylceramide synthase inhibition reduces glycosphingolipid accumulation. J Neurosci. 2021;41(12):2514-2527. PMID:33649159
- Balestrino R, et al. GBA-associated PD: The current state. Nat Rev Neurol. 2020;16(11):642-654. PMID:32989278