Objective: To characterize presenilin 1 gene (PSEN1) variants which can cause parkinsonism.

Background: Variants in PSEN1 are associated with early onset Alzheimer’s disease mainly due to dysfunction of gamma-secretase activity in amyloid-beta processing. However, patients with pathogenic variants in PSEN1 can manifest with extremely variable phenotypes including parkinsonism, spastic paraparesis, myoclonus and epileptic seizures.

Method: Data were obtained from PubMed search using terms of “presenilin 1“ and “parkinsonism”, and patients with parkinsonism or extrapyramidal signs with precise genetic information were included. Correlation between clinical symptoms and locus of PSEN1 variants were analyzed.

Results: 35 eligible patients from 21 pedigrees were included. All patients showed parkinsonism or extrapyramidal signs, and all but one patients showed early-onset progressive dementia. PSEN1 variants were in the N-terminal chain (Arg41Ser): 1 patient (without dementia), transmembrane (TM) 1 (Pro88Leu): 1, junction between TM2 and 3 (His163Pro, His163Arg): 6, TM3 (Ser170Phe, Glu184Asp): 2, TM4 (Gly206Val): 1, junction between TM4 and 5 (Gly217Asp): 2, TM5 (Leu226Val, Ser230Asn, Met233Val): 8, TM6 (Pro264Leu, Val272Ala): 3, TM7 (Phe386Ser): 1, TM8 (Gly417Ala, Gly417Ser, Leu418Trp, Leu420Arg): 9, and TM9 (Ala434Thr): 1.

Conclusion: PSEN1 variants outside catalytic core site of gamma-secretase activity can cause parkinsonism, possibly via altered presenilin 1 control over phosphatase and tensin homolog-induced kinase 1 expression and transcription.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/role-of-presenilin-1-variants-in-parkinsonism/