Axonal degeneration as a therapeutic target in the CNS

Lingor, Paul; Koch, Jan Christoph; Tönges, Lars; Bähr, Mathias

doi:10.1007/s00441-012-1362-3

Cited by 109 publications

(83 citation statements)

References 220 publications

(273 reference statements)

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“…In addition, within the context of proteinopathies, in which the degradation and removal of abnormal proteins malfunction, both are linked with considerable certainty to the pathogenic process, because the breakdown of cellular mechanisms for degrading and clearing abnormal tau and a-synuclein make them ultimately deleterious to neuronal equilibrium (Chung et al 2001;Ciechanover 2005;Olanow and McNaught 2006;Rubinsztein 2006;Lim and Tan 2007;Upadhya and Hegde 2007a,b;Pan et al 2008;Lehman 2009;Kovacech et al 2010;Ebrahimi-Fakhari et al 2012;Kopeikina et al 2012;Tai et al 2012). There is also evidence that intra-axonal a-synuclein and intraneuronal tau aggregates are associated with axonopathy (Irizarry et al 1998;Saha et al 2004;Duda et al 2006;Stokin and Goldstein 2006;Orimo et al 2008;Kanazawa et al 2011;Lingor et al 2012;Lamberts et al 2015), cell membrane dysfunction (Tsigelny et al 2012), or cellular dysfunction (Dugger and Dickson 2010). Depending on study design, some experimental models display motor impairment, cognitive impairment, or deficits in neuronal excitability and/or cell loss (Giasson et al 2002;Sydow et al 2011;Volpicelli-Daley et al 2011;Luk et al 2012a;Sacino et al 2014;Brelstaff et al 2015;Ozcelik et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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

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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Section: Discussionmentioning

confidence: 99%

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

105

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“…Traumatic brain insult can lead to injury in both grey and white matter by application of severe physical pressure on neuronal cell bodies and axons, leading to disrupted cell integrity, such as rupture and shearing. Axonal injury can lead to Wallerian degeneration and related processes [82], while severe white matter disturbance can also include injury to non-neuronal cells that support axonal and synaptic functioning, thereby affecting axon survival [81]. Non-traumatic insults can lead to structural brain injury via disruption of metabolic needs or other vital cell mechanisms in both grey and white matter [81].…”

Section: Aetiology-related Injurymentioning

confidence: 99%

Structural brain injury in patients with disorders of consciousness: A voxel-based morphometry study

et al. 2016

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Main objective: Disorders of consciousness (DOC; encompassing coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state minus/plus (MCS-/+)) are associated with structural brain injury. The extent of this damage remains poorly understood and merits a detailed examination using novel analysis techniques. Research design/methods and procedures: This study used voxel-based morphometry (VBM) on structural magnetic resonance imaging scans of 61 patients with DOC to examine grey and white matter injury associated with DOC, time spent in DOC, aetiology and diagnosis. Main outcomes and results: DOC and time spent in DOC were found to be associated with widespread structural brain injury, although the latter did not correlate strongly with injury in the right cerebral hemisphere. Traumatic, as compared to non-traumatic aetiology, was related to more injury in the brainstem, midbrain, thalamus, hypothalamus, basal forebrain, cerebellum, and posterior corpus callosum. Potential structural differences were found between VS/ UWS and MCS and between MCS-and MCS+, but need further examination. Conclusions: The findings indicate that both traumatic and non-traumatic DOC are associated with widespread structural brain injury, although differences exist that could lead to aetiologyspecific treatment strategies. Furthermore, the high degree of atrophy occurring after initial brain injury prompts the development and use of neuroprotective techniques to potentially increase patients' chances of recovery. KeywordsVegetative state/unresponsive wakefulness syndrome, minimally conscious state, structural brain injury, voxel-based morphometry History

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“…The walls of the cysts are formed by enlargement of the perineural nerve root sheaths, resulting in alteration of the environment around the spinal nerve root fibers. This alteration causes malfunction of the involved spinal nerve root fibers, similar to axonal transport dysfunction [6]. This malfunction differs from malfunction associated with compression against adjacent bone or other nerve…”

mentioning

confidence: 99%

Reconstruction of nerve root sheaths for sacral extradural spinal meningeal cysts with spinal nerve root fibers

Sun

Wang

et al. 2013

Sci. China Life Sci.

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This study analyzed the clinical characteristics and outcomes of sacral extradural spinal meningeal cysts with spinal nerve root fibers treated by reconstruction of the nerve root sheaths. The relationships between the cysts and spinal nerve root fibers were examined microscopically, the cysts were partially excised, and the defects were oversewn to reconstruct the nerve root sheaths. The Improved Japanese Orthopedic Association (IJOA) scoring system was used to evaluate preoperative and postoperative neurological function. Thirty-eight patients were included in this study, with a mean age of 41.4±15.57 years. The mean IJOA score was 18.8±1.32 preoperatively and 19.6±0.65 postoperatively, which was a significant difference (t=-3.77, P=0.001). These results indicate a significant improvement in neurological function after surgery. The most significant improvement in neurological function was sensation (z=-2.86, P=0.004), followed by bowel/bladder function (z=-2.31, P=0.02). The pathophysiological mechanism underlying the formation of SESMCs with SNRFs is congenital weakness of the nerve root sheath [3]. High hydrostatic pressure generated by upright walking and a ball-valve effect result in cyst enlargement [3][4][5]. The walls of the cysts are formed by enlargement of the perineural nerve root sheaths, resulting in alteration of the environment around the spinal nerve root fibers. This alteration causes malfunction of the involved spinal nerve root fibers, similar to axonal transport dysfunction [6]. This malfunction differs from malfunction associated with compression against adjacent bone or other nerve

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Axonal degeneration as a therapeutic target in the CNS

Cited by 109 publications

References 220 publications

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

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

Structural brain injury in patients with disorders of consciousness: A voxel-based morphometry study

Reconstruction of nerve root sheaths for sacral extradural spinal meningeal cysts with spinal nerve root fibers

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