Biology subjects

Sipple, K.

Publications and source records attributed to Sipple, K..

3 recordsLinked to original sources

bioRxiv2026

System-wide profiling reveals metabolic alterations in a G2019S LRRK2 knockin mouse model of Parkinson's disease: systemic depletion of pyrimidine nucleosides

G2019S LRRK2 is the most common cause of familial Parkinsons disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.

neuroscience↗

bioRxiv2024

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein

Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinsons disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra. Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate -synuclein (-syn) secretion via exosomes. However, the relationship between ATP13A2 and -syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating -syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of -syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of -syn pathology. In this study, we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse -syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, extent and spread of -syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by -syn PFFs in WT and KO mice but was significantly higher in ATP13A2 KO mice due to pre-existing gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by -syn PFFs in WT or KO mice after 6 months. Although -syn PFFs induce an increase in lysosomal number in the substantia nigra in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of ATP13A2 genotype. Our study evaluating the spread of -syn pathology reveals no exacerbation of -syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in -syn clearance or propagation in vivo.

neuroscience↗

bioRxiv2024

Adult-Onset Deletion of ATP13A2 in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities

Although most cases of Parkinsons disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of PD. A surprising number of familial PD-linked genes and PD risk genes are involved in intracellular trafficking and protein degradation. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome (KRS), hereditary spastic paraplegias (HSPs), neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis (ALS). Given the severe effects of ATP13A2 mutations in humans, it is surprising that ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages. This discrepancy between human subjects and rodents makes it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

neuroscience↗