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Alzheimer, Parkinson Disease Share Protective Association at HLA Locus

Protective HLA-DRB1*04 subtypes bind strongly to aggregation-prone tau PHF6 sequence when acetylated at K311

By Elana Gotkine HealthDay Reporter

FRIDAY, Sept. 8, 2023 (HealthDay News) — Alzheimer disease (AD) and Parkinson disease (PD) share the same protective association at the human leukocyte antigen (HLA) locus, according to a study published online Aug. 29 in the Proceedings of the National Academy of Sciences.

Yann Le Guen, Ph.D., from Stanford University in California, and colleagues examined HLA associations in more than 176,000 individuals with PD and AD compared to controls across multiancestry groups.

The researchers found that the diseases shared the same protective association at the HLA locus. The association was best accounted for by the hierarchical protective effects of HLA-DRB1*04 subtypes, which were strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07 and intermediate with HLA-DRB1*04:01 and HLA-DRB1*04:03. In postmortem brains, the same signal was associated with reduced neurofibrillary tangles; the signal was also associated with reduced tau levels in cerebrospinal fluid and with increased Aβ42 to a lesser extent. When acetylated at a lysine (K311), protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence.

“Our results also open the possibility that targeting tau epitopes containing acetylated-K311 through chimeric antigen receptor T cells or antibodies could have therapeutic values,” the authors write.

Two authors filed a patent application on this discovery.

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