Dylan Noble

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over 6 million individuals worldwide.¹ A diagnosis of PD is made through a combination of history taking, neurological exam, and response to dopamine therapy.³ At the cellular level, PD is characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNc).^2,3 The resulting decrease in striatal dopamine levels causes aberrant functioning of the basal ganglia signaling pathway, which disrupts normal voluntary motor functions.³ More specifically, PD is characterized by loss of motor function that manifests as bradykinesia, rigidity, and resting tremor.¹ As these symptoms progress and deficits accumulate, quality of life is markedly decreased over several decades.¹ With the prevalence of PD expected to double by 2040, the discovery of neuroprotective treatments that prevent the underlying neuron death is an urgent medical need.² Current treatments for PD only address symptoms by increasing striatal dopamine levels, most commonly through a combination of Levodopa-Carbidopa therapy, as neuroprotective drugs do not yet exist.³ Although exposure to toxins and head trauma are thought to contribute to sporadic PD, genetic mutations account for almost 10% of total PD cases.² In particular, mutations in the GBA gene coding for the enzyme glucocerebrosidase (GCase) are found in 5-10% of all genetically linked PD cases.^2,5 GBA mutations have been linked to accumulation of  alpha-synuclein, a protein known to initiate death of SNc dopaminergic neurons.⁴ As such, development of neuroprotective treatments that target dysfunctional GCase and consequent alpha-synuclein accumulation, would be a crucial advancement in finding a cure for PD.

Objective: This literature review explored the linkage of GBA gene mutations and their contribution to PD development, as well as potential drug therapy.

Search Methods: The online PubMed database was used to search articles from 2017-2023 using the keywords “GBA gene”, “Parkinson’s” and “Ambroxol”.

Results: Cell model studies found that the heterozygous GBA mutations N370S and L444P result in a misfolded GCase enzyme that impairs lysosomal function, causing accumulation of toxic alpha-synuclein oligomers.⁷ Mutant GCase binds to and occupies LAMP2A lysosomal surface receptors, preventing the uptake and degradation of alpha-synuclein into lysosomes via chaperone medicated autophagy (CMA).⁶ L444P PD patient fibroblast cell lines also showed increased levels of short chain ceramides, sphingomyelin, and hexosylceramide in lysosomal lipid membranes.⁸ This altered lipid profile prevented the stabilization of LAMP2A receptors, contributing to decreased CMA of alpha-synuclein.⁸

Expanding areas of PD treatment aim to address neuronal cell death, and one such candidate is the drug Ambroxol. Used to thin mucus in respiratory illness, Ambroxol is a chaperone of GCase and could help to upregulate GCase activity in PD.⁹ In an N370S Cell model, Ambroxol treatment induced a 55% increase in GCase activity and a significant decrease in alpha-synuclein.⁹ In dopamine depleted rats, Ambroxol recovered GCase activity, striatal dopamine levels, and improved motor function.¹⁰ In a human trial among PD patients, Ambroxol was able to successfully cross the BBB and interact with GCase.¹¹ Additionally, the drug was very well tolerated among the study participants, producing few adverse effects.¹¹

Conclusion: Studies have found that GBA mutations and resulting mutant GCase has a direct mechanistic link to alpha-synuclein accumulation and PD development via disruption of normal lysosomal function. Moreover, Ambroxol therapy was found to have the capability to restore GCase function, reduce alpha-synuclein accumulation, and prevent nigral cell death. Future research is required; however, Ambroxol has potential to become a treatment option for mutant GBA induced PD.

Works Cited.

1.  Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 2021;20(5):385-397.
2. Simon DK, Tanner CM, Brundin P. Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clin Geriatr Med. 2020;36(1):1-12.
3. Bloem BR, Okun MS, Klein C. Parkinson’s disease. 2021;397(10291):2284-2303.
4. Zhang PL, Chen Y, Zhang CH, Wang YX, Fernandez-Funez P. Genetics of Parkinson’s disease and related disorders. J Med Genet. 2018;55(2):73-80.
5. Riboldi GM, Di Fonzo AB. GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches. 2019;8(4).
6. Kuo SH, Tasset I, Cheng MM, et al. Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy. Sci Adv.2022;8(6):eabm6393
7. Navarro-Romero A, Fernandez-Gonzalez I, Riera J, et al. Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology. NPJ Parkinsons Dis. 2022;8(1):126.
8. Galvagnion C, Marlet FR, Cerri S, Schapira AHV, Blandini F, Di Monte DA. Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation. 2022;145(3):1038-1051.
9. Yang SY, Taanman JW, Gegg M, Schapira AHV. Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model. Hum Mol Genet. 2022;31(14):2396-2405.
10. Mishra A, Krishnamurthy S. Neurorestorative effects of sub-chronic administration of ambroxol in rodent model of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(3):429-444.
11. Mullin S, Smith L, Lee K, et al. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020;77(4):427-434