α-Synuclein Pathology and Reduced Neurogenesis in the Olfactory System Affect Olfaction in a Mouse Model of Parkinson's Disease
Abstract
Parkinson's disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6–7 and 12–14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12–14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12–14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 03, 2023
- Source ID
- 10.1523/jneurosci.1526-22.2022
Entities
People
- Betül Yücel
- Bowen Brennan
- Charles A Greer
- D J Vidyadhara
- Eduardo Martín-López
- Kimberly Han
- Leah E. Harmon
- Natalie Spence
- Ryan M. Hsu
- Sarah J. Meller
- Sreeganga S Chandra
- Teresa Liberia
Organizations
- National Institute of Neurological Disorders and Stroke
- National Institute on Deafness and Other Communication Disorders
- United States Department of Defense