Details

Autor(en) / Beteiligte

• Patterson, Joseph R.
• Duffy, Megan F.
• Kemp, Christopher J.
• Howe, Jacob W.
• Collier, Timothy J.
• Stoll, Anna C.
• Miller, Kathryn M.
• Patel, Pooja
• Levine, Nathan
• Moore, Darren J.
• Luk, Kelvin C.
• Fleming, Sheila M.
• Kanaan, Nicholas M.
• Paumier, Katrina L.
• El-Agnaf, Omar M.A.
• Sortwell, Caryl E.

Titel

Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils

Ist Teil von

• Neurobiology of disease, 2019-10, Vol.130, p.104525-104525, Article 104525

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 μg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 μg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies. •Increasing the amount of alpha-synuclein preformed fibrils increases the magnitude of nigrostriatal neurodegeneration.•Loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra occurs bilaterally by 6 months post-injection.•Ipsilateral tyrosine hydroxylase immunoreactive neuron loss precedes contralateral loss.•Bilateral intrastriatal injections of preformed fibrils does not increase degeneration compared to unilateral injections.