Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria

Dickson, Dennis W.; Braak, Heiko; Duda, John E.; Duyckaerts, Charles; Gasser, Thomas; Halliday, Glenda M.; Hardy, John; Leverenz, James B.; Tredici, Kelly Del; Wszołek, Zbigniew K.; Litvan, Irene

doi:10.1016/s1474-4422(09)70238-8

Cited by 759 publications

(603 citation statements)

References 89 publications

Supporting

Mentioning

563

Contrasting

Unclassified

Order By: Relevance

“…26 Previous neuropathological examination reported the presence of a-synuclein-positive Lewy bodies in the brain of most (G2019S) LRRK2 PD patients. 11,12,14 However, SN neuronal loss in the absence of Lewy bodies was also found in some PD patients with (G2019S) LRRK2 mutation.…”

Section: Discussionmentioning

confidence: 99%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

153

151

View full text Add to dashboard Cite

(G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve-to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser 257 , and protein expression of active phospho-MKK4 Ser257 was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK Thr183/Tyr185 and phospho-c-Jun Ser63 , downstream targets of phospho-MKK4 Ser257 , was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun Ser63 , and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4-JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice.

show abstract

Section: Discussionmentioning

confidence: 99%

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Yh²,

et al. 2012

Cell Death Differ

153

151

View full text Add to dashboard Cite

show abstract

“…One of the main features affecting these patients includes a slowness of initiation of voluntary movement with a progressive reduction in speed and amplitude of sequential motor tasks [17,18]. For a long time, PD was thought to involve a relatively simple neuropathological process primarily centered on the loss of dopaminergic neurons in the SN.…”

Section: Clinical and Pathological Aspectsmentioning

confidence: 99%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

View full text Add to dashboard Cite

“…52 In apparent later stages of PD, Lewy pathology is also scattered throughout the cerebral cortex, amygdala and hippocampus. 53,54 Retinal dopaminergic also has been reported to decline, but Lewy pathology was not identified. 55 The nucleus basalis of Meynert is a prominent site of Lewy pathology and cell loss in PD patients.…”

Section: Introductionmentioning

confidence: 99%

The pathology roadmap in Parkinson disease

Surmeier¹,

Sulzer

2013

Prion

View full text Add to dashboard Cite

Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria

Cited by 759 publications

References 89 publications

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

The pathology roadmap in Parkinson disease

Contact Info

Product

Resources

About