PSAP (prosaposin) variants

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Yutaka Oji, Taku Hatano, Manabu Funayama and Nobutaka Hattori (senior author) of Juntendo University and other Japanese centres, with Matthew Farrer and a Taiwanese group (Brain 143:1190-1205, April 2020). I did not read the funding statement.

What happened

PSAP codes for prosaposin, a precursor that is cut into four helper proteins called saposins (A–D). They help lysosomal enzymes break down fats. Faults in PSAP cause rare inherited lysosomal storage diseases, the family that includes Gaucher disease and GBA (landmark 233 is the group-level study).

Oji et al. screened Japanese patients and found three damaging changes in the saposin D region in three families with dominant Parkinson's. Exome sequencing found no variant in known Parkinson's or storage-disease genes. In a case-control study of Japan and Taiwan, two intron variants (rs4747203 and rs885828) were more frequent in sporadic patients. Patient skin cells and induced stem-cell neurons showed build-up of autophagic vacuoles, impaired autophagy flux and clumped synuclein. A mouse with a saposin D change had progressive movement decline and loss of dopamine neurons.

Replication:

• Chen et al. (Mol Neurobiol 2021) used exome sequencing in 400 dominant and 300 sporadic Chinese patients. Rare likely-damaging variants were in 0.75% and 1.33%, but the burden signal was in saposin C, and rs4747203 was linked to reduced, not raised, risk.
• Sosero et al. (IPDGC and McGill, Brain 2020;143:e72) sequenced PSAP in 4,132 patients and 4,470 controls and checked the 2019 European GWAS: no burden of rare variants in saposin D or the other saposins, no association for common variants, and no known pathogenic saposin D variant found. The two intron variants showed no association in Europeans (P = 0.76 for one). They also point out that the saposin D variants only partly tracked with disease in Oji's families (carriers without Parkinson's, including an obligate carrier parent).
• Further Brain letters: Facchi et al. (Italy, 2020), "Saposin D variants are not a common cause of familial Parkinson's disease among Italians"; Chao et al. (Singapore, 2021) and Zhao et al. (Chinese mainland, 2021), contents not read; each drew a reply from Oji and colleagues.

Why it moved us toward a cure

It adds a lysosome gene on the path where GBA sits. If cells that cannot recycle fats accumulate synuclein, the lysosome is a target. Saposin C activates the enzyme made by GBA (stated in the Sosero letter), so the two genes act on the same step.

Outcome

Open, leaning to unreplicated. The family and intron findings have not been confirmed in the larger European and Chinese checks I could read, and eight comment-and-reply items are attached to the paper (Europe PMC). No correction or retraction is recorded for Oji 2020 or Chen 2021 (Crossref). No therapy is built on it.

Sources

• Oji et al., Brain 2020;143:1190–1205, DOI 10.1093/brain/awaa064
• Chen et al., Mol Neurobiol 2021;58:1583–1592, DOI 10.1007/s12035-020-02218-4
• Correspondence in Brain: Sosero et al. 2020, DOI 10.1093/brain/awaa214, PMC7523699 · Facchi et al. 2020, DOI 10.1093/brain/awaa213 · Chao et al. 2021, DOI 10.1093/brain/awaa358 · Zhao et al. 2021, DOI 10.1093/brain/awaa391 · Oji et al. replies, DOI 10.1093/brain/awaa356
• Not yet verified: Oji's cohort sizes and mutation names; the content of the Chao and Zhao letters and the replies; funding.