Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease

Adv. Drug Deliv. Rev. 2022 Aug;187:114402. doi: 10.1016/j.addr.2022.114402.

PMID: 35764179

Mia Horowitz, Hila Braunstein, Ari Zimran

Highlights: The present review will elaborate on the biology of Gaucher disease (GD), its association with Parkinson's disease (PD) and related disorders, and discuss the possible mechanisms underlying this association.

Abstract

Background: Because they are involved in secretion, plasma membrane repair, cell signaling, and energy metabolism, lysosomes are crucial in preserving normal cellular homeostasis. About 50 rare diseases known as lysosomal storage disorders (LSDs) result from mutations in the genes that code for lysosomal proteins and cause lysosomal dysfunction. The deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), which results from biallelic mutations in the GBA1 gene, is the underlying cause of Gaucher disease (GD), an autosomal recessive disorder and one of the most prevalent LSDs. Reduced GCase activity causes glucosylceramide (GlcCer) to build up, which lysosomal acid ceramidase deacylates into the toxic metabolite glucosylshpingosine (GlcSph). The majority of GBA1 variants are identified in the ER as being misfolded, where retention for refolding attempts causes stress and activates the Unfolded Protein Response stress response (UPR). Whether the central nervous system is primarily involved determines the different clinical subtypes of GD. The nonneuropathic kind of GD is type 1 (GD1), but this classification is challenged by the recent discovery that GD is linked to the onset of parkinsonism. Patients who have GD1 and are GBA1 mutation carriers are susceptible to the onset of parkinsonian symptoms. The movement abnormality that results from Parkinson disease (PD), the second most common neurological disease, causes premature death of the patients. α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites, as well as the death of dopaminergic neurons, are the hallmark pathologies of Parkinson's disease (PD) and associated disorders, which are commonly referred to as synucleinopathies. Although PD is typically sporadic, in about 5–10% of cases, pathogenic mutations in a rising number of genes cause the disease. Mutations in GBA1 are the most frequent genetic source of PD. Two explanations for this connection have been put forth: (A) a "gain of function" mechanism, in which mutant GCase (protein) aids in the formation of aggregates and the onset of PD; and (B) a "haploinsufficiency" ("loss of function") model, which contends that one normal GBA1 allele is insufficient to carry sufficient GCase activity and that functional GCase deficiency impedes α-synuclein metabolism. The development of PD disease is caused by the buildup of α-synuclein, which is further enhanced by lysosomal dysfunction, impaired autophagy, and impaired mitophagy.

Objective: The biology of GD, its link to PD and other related disorders, and potential mechanisms underlying this association will all be covered in detail in the current review.

Keywords: Gaucher disease, Glucocerebrosidase (GCase), Misfolding, Parkinson disease, Unfolded Protein Response (UPR)