TY - JOUR
T1 - Heterozygous loss of Engrailed-1 and α-synucleinopathy (En1/SYN)
T2 - A dual-hit preclinical mouse model of Parkinson's disease, analyzed with artificial intelligence
AU - Stetzik, Lucas
AU - Mercado, Gabriela
AU - Steiner, Jennifer A.
AU - Lindquist, Allison
AU - Gilliland, Carla
AU - Schulz, Emily
AU - Meyerdirk, Lindsay
AU - Smith, Lindsey
AU - Molina, Jeremy
AU - Moore, Darren J.
N1 - Publisher Copyright:
© 2024
PY - 2024/10/1
Y1 - 2024/10/1
N2 - In this study, we develop and validate a new Parkinson's disease (PD) mouse model that can be used to better understand how the disease progresses and to test the effects of new, potentially disease-modifying, PD therapies. Our central hypothesis is that mitochondrial dysfunction intercalates with misfolded α-synuclein (α-syn) accumulation in a vicious cycle, leading to the loss of nigral neurons. Our hypothesis builds on the concept that PD involves multiple molecular insults, including mitochondrial dysfunction and aberrant α-syn handling. We predicted that mitochondrial deficits, due to heterozygous loss of Engrailed-1 (En1+/−), combined with bilateral injections of pathogenic α-syn fibrils (PFFs), will act to generate a highly relevant PD model – the En1/SYN model. Here, En1+/− mice received bilateral intrastriatal stereotaxic injections of either PBS or α-syn fibrils and were analyzed using automated behavioral tests and deep learning-assisted histological analysis at 2, 4, and 6 months post-injection. We observed significant and progressive Lewy body-like inclusion pathology in the amygdala, motor cortex, and cingulate cortex, as well as the loss of tyrosine hydroxylase-positive (TH+) cells in the substantia nigra. The En1/SYN model also exhibited significant motor impairments at 6 months post-injection, which were however not exacerbated as we had expected. Still, this model has a comprehensive number of PD-like phenotypes and is therefore superior when compared to the α-syn PFF or En1+/− models alone.
AB - In this study, we develop and validate a new Parkinson's disease (PD) mouse model that can be used to better understand how the disease progresses and to test the effects of new, potentially disease-modifying, PD therapies. Our central hypothesis is that mitochondrial dysfunction intercalates with misfolded α-synuclein (α-syn) accumulation in a vicious cycle, leading to the loss of nigral neurons. Our hypothesis builds on the concept that PD involves multiple molecular insults, including mitochondrial dysfunction and aberrant α-syn handling. We predicted that mitochondrial deficits, due to heterozygous loss of Engrailed-1 (En1+/−), combined with bilateral injections of pathogenic α-syn fibrils (PFFs), will act to generate a highly relevant PD model – the En1/SYN model. Here, En1+/− mice received bilateral intrastriatal stereotaxic injections of either PBS or α-syn fibrils and were analyzed using automated behavioral tests and deep learning-assisted histological analysis at 2, 4, and 6 months post-injection. We observed significant and progressive Lewy body-like inclusion pathology in the amygdala, motor cortex, and cingulate cortex, as well as the loss of tyrosine hydroxylase-positive (TH+) cells in the substantia nigra. The En1/SYN model also exhibited significant motor impairments at 6 months post-injection, which were however not exacerbated as we had expected. Still, this model has a comprehensive number of PD-like phenotypes and is therefore superior when compared to the α-syn PFF or En1+/− models alone.
KW - AI
KW - Alpha synuclein
KW - Behavior
KW - engrailed1
KW - Preclinical
UR - http://www.scopus.com/inward/record.url?scp=85202519690&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85202519690&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2024.106647
DO - 10.1016/j.nbd.2024.106647
M3 - Article
C2 - 39187209
AN - SCOPUS:85202519690
SN - 0969-9961
VL - 200
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 106647
ER -