Exploring Uncharted Territory: Genetically Determined Sex Differences in Parkinson's Disease

Klein, Christine; König, Inke R.

doi:10.1002/ana.26091

Cited by 4 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another parallel between meth-induced neurotoxicity and PD is the presence of a sex difference, with female subjects displaying relative resistance in both cases. In humans, the incidence of idiopathic PD is approximately 1.5x more common in men than women, and has an earlier onset [73]. Given the similarities between meth neurotoxicity and PD, it is perhaps not surprising that meth abuse is associated with an increased the risk for developing PD [74][75][76][77][78][79], although see [80,81].…”

Section: Discussionmentioning

confidence: 99%

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice

Pilski,

Graves

2023

IJMS

View full text Add to dashboard Cite

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice

Pilski,

Graves

2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Notably, there are also sex differences in terms of disease progression ( 18 ) and response to current treatment ( 19 – 21 ). The role of genetics on these sex differences is only beginning to be explored ( 22 ). Finding new treatment options, including treatment options that account for differences between females and males, will be key to improving the quality of life of individuals living with PD.…”

Section: Introductionmentioning

confidence: 99%

Lipid-lowering drug targets and Parkinson's disease: A sex-specific Mendelian randomization study

Zhao

Taliun

2022

Front. Neurol.

View full text Add to dashboard Cite

Parkinson's disease (PD) affects millions of individuals worldwide, and it is the second most common late-onset neurodegenerative disorder. There is no cure and current treatments only alleviate symptoms. Modifiable risk factors have been explored as possible options for decreasing risk or developing drug targets to treat PD, including low-density lipoprotein cholesterol (LDL-C). There is evidence of sex differences for cholesterol levels as well as for PD risk. Genetic datasets of increasing size are permitting association analyses with increased power, including sex-stratified analyses. These association results empower Mendelian randomization (MR) studies, which, given certain assumptions, test whether there is a causal relationship between the risk factor and the outcome using genetic instruments. Sex-specific causal inference approaches could highlight sex-specific effects that may otherwise be masked by sex-agnostic approaches. We conducted a sex-specific two-sample cis-MR analysis based on genetic variants in LDL-C target encoding genes to assess the impact of lipid-lowering drug targets on PD risk. To complement the cis-MR analysis, we also conducted a sex-specific standard MR analysis (using genome-wide independent variants). We did not find evidence of a causal relationship between LDL-C levels and PD risk in females [OR (95% CI) = 1.01 (0.60, 1.69), IVW random-effects] or males [OR (95% CI) = 0.93 (0.55, 1.56)]. The sex-specific standard MR analysis also supported this conclusion. We encourage future work assessing sex-specific effects using causal inference techniques to better understand factors that may contribute to complex disease risk differently between the sexes.

show abstract

“…They observed that repeated meth exposure produced SN and LC axonal deficits prior to somatic loss in males, consistent with a dying-back pattern of degeneration, whereas female mice were resistant to chronic methinduced degeneration. Interestingly, the pattern of degeneration observed in male mice and the sex difference paralleled in Parkinson's disease [35] and patients with a history of meth abuse have been reported to lead to an increased risk of developing Parkinson's disease [36]. In addition, exposure to meth also increases the risk of Alzheimer's disease, as LC degeneration has been linked to pathogeneses associated with this disease [37].…”

mentioning

confidence: 99%

Neurodegenerative Disease: From Molecular Basis to Therapy

Ricci

2024

IJMS

View full text Add to dashboard Cite

show abstract

Exploring Uncharted Territory: Genetically Determined Sex Differences in Parkinson's Disease

Cited by 4 publications

References 24 publications

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice

Lipid-lowering drug targets and Parkinson's disease: A sex-specific Mendelian randomization study

Neurodegenerative Disease: From Molecular Basis to Therapy

Contact Info

Product

Resources

About