Spinal cord lesions in sporadic Parkinson’s disease

Tredici, Kelly Del; Braak, Heiko

doi:10.1007/s00401-012-1028-y

Cited by 132 publications

(142 citation statements)

References 182 publications

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“…Although N2a cells are not dopaminergic, Parkinson's disease is now well known to extend beyond the ventral midbrain, as mentioned earlier. Many extranigral brain regions, including the spinal cord, are affected with synuclein inclusions (Braak et al 2002;Braak et al 2003;Del Tredici and Braak 2012). In the studies discussed below, we examined the N2a response to acute, severe proteotoxic stress in a cellular model of synergistic neurodegeneration.…”

Section: Even Long-term Stress Can Elicit Adaptationsmentioning

confidence: 99%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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ᮀ Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.

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Section: Even Long-term Stress Can Elicit Adaptationsmentioning

confidence: 99%

Adaptation and Sensitization to Proteotoxic Stress

Leak

2013

Dose-Response

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Section: Spread Of Pathological A-synuclein Lesions In Pdmentioning

confidence: 99%

“…Moreover, this system can temporarily reduce the conduction of incoming pain signals while raising attention levels and placing the organism's motor neurons in a heightened state of readiness (Fig. 4, light purple) (Nieuwenhuys 1996;Del Tredici and Braak 2012). It is possible that descending projections from the involved supraspinal level-setting nuclei (beginning in stage 2 and continuing in stage 3) transfer or disseminate aggregated a-synuclein in an anterograde direction to axons in the spinal cord, including lateral portions of layers 7 (viscerosensory/visceromotor autonomic centers, intermediolateral nucleus [IML], sacral parasympathetic nucleus [SPS]), 1 (nociception), and 9 (somatomotor system) (Fig.…”

Section: Spread Of Pathological A-synuclein Lesions In Pdmentioning

confidence: 99%

“…4). These features may account for the noticeable differences between the regional distribution patterns and progression of both pathologies: Although abnormal tau remains virtually confined to the CNS in AD (Arnold et al 2010;Braak and Del Tredici 2015a), synucleinopathy in PD develops in all divisions of the nervous system (CNS, ENS, and PNS) (Beach et al 2010;Del Tredici et al 2010;Del Tredici and Braak 2012; Malek et al 2014).Intracerebrally, the PD-associated process consistently begins (PD stage 1) in the OB (chiefly in the anterior olfactory nucleus) and/ or in the dmX (Fig. 4, dark purple) (Pearce et al 1995;Hawkes et al 1999;Del Tredici et al 2002;Braak et al 2003a;Bloch et al 2006;Fujishiro et al 2008;Beach et al 2009;Braak and Del Tredici 2009;Markesbery et al 2009).…”

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confidence: 99%

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Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

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105

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Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

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“…In PD, diencephalon-spinal dopaminergic neuronal pathways could be altered [50], and α-synuclein and Lewy bodies have been observed in the spinal cord of patients with PD [51]. However, it is unlikely that SCS could have a direct impact on these neuronal abnormalities to improve motor behavior.…”

Section: Pathophysiologymentioning

confidence: 99%

Spinal Stimulation for Movement Disorders

et al. 2014

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Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.

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Spinal cord lesions in sporadic Parkinson’s disease

Cited by 132 publications

References 182 publications

Adaptation and Sensitization to Proteotoxic Stress

Adaptation and Sensitization to Proteotoxic Stress

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Spinal Stimulation for Movement Disorders

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