Abstract
Parkinson’s disease is characterized by degeneration of substantia nigra dopamine neurons and by intraneuronal aggregates, primarily composed of misfolded α-synuclein. The α-synuclein aggregates in Parkinson’s patients are suggested to first appear in the olfactory bulb and enteric nerves and then propagate, following a stereotypic pattern, via neural pathways to numerous regions across the brain. We recently demonstrated that after injection of either mouse or human α-synuclein fibrils into the olfactory bulb of wild-type mice, α-synuclein fibrils recruited endogenous α-synuclein into pathological aggregates that spread transneuronally to over 40 other brain regions and subregions, over 12 months. We previously reported the progressive spreading of α-synuclein aggregates, between 1 and 12 months following α-synuclein fibril injections, and now report how far the pathology has spread 18- and 23-month post-injection in this model. Our data show that between 12 and 18 months, there is a further increase in the number of brain regions exhibiting pathology after human, and to a lesser extent mouse, α-synuclein fibril injections. At both 18 and 23 months after injection of mouse and human α-synuclein fibrils, we observed a reduction in the density of α-synuclein aggregates in some brain regions compared to others at 12 months. At 23 months, no additional brain regions exhibited α-synuclein aggregates compared to earlier time points. In addition, we also demonstrate that the induced α-synucleinopathy triggered a significant early neuron loss in the anterior olfactory nucleus. By contrast, there was no loss of mitral neurons in the olfactory bulb, even at 18 month post-injection. We speculate that the lack of continued progression of α-synuclein pathology is due to compromise of the neural circuitry, consequential to neuron loss and possibly to the activation of proteolytic mechanisms in resilient neurons of wild-type mice that counterbalances the spread and seeding by degrading pathogenic α-synuclein.
Highlights
Parkinson’s disease (PD) is characterized by the accumulation of intraneuronal inclusions of alpha-synuclein (α-syn) in the somata (Lewy bodies) or in neurites (Lewy neurites) of neurons [18]. α-Syn, as a presynaptic protein, is natively unfolded, but in Lewy pathology, α-syn misfolds into amyloid fibrils that form the hallmark inclusions of PD [11, 14]
We recently demonstrated that pathology induced by unilateral injection of human or mouse wild-type α-syn pre-formed fibrils (PFFs), designated huPFFs or mPFFs, respectively, into the olfactory bulb (OB) of 3-month-old wild-type (WT) mice can propagate sequentially over multiple synaptic relays, reaching numerous ipsi- and contralateral brain regions after 12 months, including brain stem areas (e.g., a few aggregates in the substantia nigra (SN), locus coeruleus (LC), and raphe nucleus (RN))
We hypothesise that following injection of either huPFFs or mPFFs α-syn into the OB of wild-type mice, α-syn aggregation in olfactory pathways would lead to neuron loss, which could contribute to the olfactory deficits previously described [59]
Summary
Parkinson’s disease (PD) is characterized by the accumulation of intraneuronal inclusions of alpha-synuclein (α-syn) in the somata (Lewy bodies) or in neurites (Lewy neurites) of neurons [18]. α-Syn, as a presynaptic protein, is natively unfolded, but in Lewy pathology, α-syn misfolds into amyloid fibrils that form the hallmark inclusions of PD [11, 14]. Based on the ability of misfolded α-syn to aggregate and further recruit endogenous α-syn, the α-syn transmission hypothesis posits that misfolded α-syn can form proteopathic seeds that template normal α-syn to misfold, undergo intra-axonal transport to other brain regions, and propagate synucleinopathies through iterative repetition of this process, perpetuating a vicious cycle [16, 20, 31, 40, 46]. This process is suggested to underlie the spatio-temporal progression of α-syn pathology observed in PD brains. We further define the consequences of these huPFFs and mPFFs injections into the OB and determine, first, the extent of α-syn pathology at 18 and 23 months after injection and second, if there is cell loss in the olfactory bulb and in the AON
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
