Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease

Ziegler, David A.; Wonderlick, Julien S.; Ashourian, Paymon; Hansen, Leslie A.; Young, Jeremy C.; Murphy, Alex J.; Koppuzha, Cecily K.; Growdon, John H.; Corkin, Suzanne

doi:10.1001/jamaneurol.2013.597

Cited by 59 publications

(49 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reduced volume of the SN has also been reported by MRI analysis of PD patients correlating with motor decline. 45,46 In concordance with earlier reports, 43 these TG mice at 4 months also had significantly lower total brain volume (Supplementary Figure S1C) compared with age-matched WT mice, but at 15 months, brain volume had recovered and was equivalent between TG and WT mice. Loss of DA-neurons and diminished SN volume was also accompanied by a substantial Comparisons between age-matched WT and TG mice, as well as between TG mice of different ages were made using Welch's t test or one-way ANOVA, and significance was measured as *Po0.05 or **Po0.01 or ***Po0.001.…”

Section: Resultssupporting

confidence: 90%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

View full text Add to dashboard Cite

Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

show abstract

Section: Resultssupporting

confidence: 90%

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

et al. 2014

View full text Add to dashboard Cite

show abstract

“…For example, in agreement with the present findings, decreased regional volume and dopaminergic neuronal density in the SN and the VTA were reported in PD (German and Manaye, 1993; Jellinger, 1991; Kashihara et al, 2011; McRitchie et al, 1997; Ziegler et al, 2013). However, most post-mortem studies of PD have examined an advanced stage of neuronal loss in which SNpc neurons are decreased by 70% or more (Hirsch et al, 1988).…”

Section: Discussionsupporting

confidence: 93%

Differential effects of intrastriatal 6-hydroxydopamine on cell number and morphology in midbrain dopaminergic subregions of the rat

Healy-Stoffel¹,

Ahmad²,

Stanford³

et al. 2014

Brain Research

View full text Add to dashboard Cite

The midbrain dopaminergic perikarya are differentially affected in Parkinson’s disease (PD). This study compared the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion model of PD on the number, morphology, and nucleolar volume of dopaminergic cells in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and retrorubral field (RRF). Adult, male rats (n=10) underwent unilateral intrastriatal infusion of 6-OHDA (12.5 μg). Lesions were verified by amphetamine-stimulated rotation 7 days post-infusion. Rats were euthanized 14 days after treatment with 6-OHDA and brains were stained with a tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain. Dopaminergic cell number and morphology in the lesioned and intact hemispheres were quantified using stereological methods. The magnitude of decrease in planimetric volume, neuronal number, cell density, and neuronal volume resulting from 6-OHDA lesion differed between regions, with the SNpc exhibiting the greatest loss of neurons (46%), but the smallest decrease in neuronal volume (13%). The lesion also resulted in a decrease in nucleolar volume that was similar in all three regions (22–26%). These findings indicate that intrastriatal 6-OHDA lesion differentially affects dopaminergic neurons in the SNpc, VTA, and RRF; however, the resulting changes in nucleolar morphology suggest a similar cellular response to the toxin in all three cell populations.

show abstract

“…The substantia nigra is located midway between the cortex and the spinal cord and has 400,000 neurons, four for every 100,000 of the brain's 100,000,000,000 neurons. When, because of the process of Parkinson, 240,000 of the neurons in the substantia nigra, 60% of the total, die, the motor symptoms of PD appear [25,26]. It's estimated that the process of PD, as distinct from its symptoms, begins years before the symptoms appear and the disease is diagnosed.…”

Section: Discussionmentioning

confidence: 99%

“…The best available answer is that PD is more than a disease of movement. Disorders including depression and lack of impulse control are common: 40% or more of all PD patients are depressed [26,27]. Also, 6.1% have impulsive reward-seeking behavior, behavior present before patients are treated, but behavior increased by dopamine agonists.…”

Section: Discussionmentioning

confidence: 99%

Famous People with Parkinson Disease

Lieberman¹,

Deep²

2015

J Neurol Neurosurg

View full text Add to dashboard Cite

In this manuscript, we assess whether the prevalence of Parkinson disease (PD) among famous people is greater than in a sample of all people. We compared the prevalence of PD in two populations: The first population included people who were named TIME magazine's Person of the Year, a contemporary measure of fame. The second population considered for analysis included people enrolled in the EuroParkinson Collaborative Study. Parkinson disease is more than a movement disorder. Depression and reward-seeking behavior are common among people with the condition. It is possible that the movement disorder symptoms of PD (with or without depression) may be preceded by a period of mania or hypomania, a surge of creative energy, or a lack of inhibition as occurs in bipolar disorder. It may be that during this surge of creative energy and reward-seeking behavior, the basis of fame is laid. TIME magazine named 54 individuals as its

show abstract

Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease

Cited by 59 publications

References 41 publications

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Differential effects of intrastriatal 6-hydroxydopamine on cell number and morphology in midbrain dopaminergic subregions of the rat

Famous People with Parkinson Disease

Contact Info

Product

Resources

About