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Role of α- and β-Synucleins in the Axonal Pathology of Parkinson's Disease and Related Synucleinopathies.

Sekigawa A, Takamatsu Y, Sekiyama K, Hashimoto M - Biomolecules (2015)

Bottom Line: In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies.However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules.Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies.

View Article: PubMed Central - PubMed

Affiliation: Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan. akio.sekigawa@zeiss.com.

ABSTRACT
Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders.

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A hypothetical sequence of the pathogenesis of α-synucleinopathies. Axonopathies may precede the pathology of neuronal cell bodies in neurodegeneration. Various morphological changes (e.g., axonal swellings, Lewy neuritis and Lewy bodies) are associated with the progress of the disease.
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biomolecules-05-01000-f001: A hypothetical sequence of the pathogenesis of α-synucleinopathies. Axonopathies may precede the pathology of neuronal cell bodies in neurodegeneration. Various morphological changes (e.g., axonal swellings, Lewy neuritis and Lewy bodies) are associated with the progress of the disease.

Mentions: Previous studies on the histopathology of the α-synucleinopathies have focused on Lewy bodies as hallmarks of the diseases. However, formation of Lewy bodies is a complicated process and the precise role of Lewy bodies in the pathogenesis of α-synucleinopathies is still unclear [7]. It is possible that it takes a long time for Lewy bodies to form in human brains [8]. This may be one reason why Lewy bodies are not found in the brains of rodent models of α-synucleinopathies whose life spans are much shorter when compared to that of humans [7]. Thus, it is likely that Lewy bodies are important for investigating the late pathogenesis of PD (Figure 1).


Role of α- and β-Synucleins in the Axonal Pathology of Parkinson's Disease and Related Synucleinopathies.

Sekigawa A, Takamatsu Y, Sekiyama K, Hashimoto M - Biomolecules (2015)

A hypothetical sequence of the pathogenesis of α-synucleinopathies. Axonopathies may precede the pathology of neuronal cell bodies in neurodegeneration. Various morphological changes (e.g., axonal swellings, Lewy neuritis and Lewy bodies) are associated with the progress of the disease.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496706&req=5

biomolecules-05-01000-f001: A hypothetical sequence of the pathogenesis of α-synucleinopathies. Axonopathies may precede the pathology of neuronal cell bodies in neurodegeneration. Various morphological changes (e.g., axonal swellings, Lewy neuritis and Lewy bodies) are associated with the progress of the disease.
Mentions: Previous studies on the histopathology of the α-synucleinopathies have focused on Lewy bodies as hallmarks of the diseases. However, formation of Lewy bodies is a complicated process and the precise role of Lewy bodies in the pathogenesis of α-synucleinopathies is still unclear [7]. It is possible that it takes a long time for Lewy bodies to form in human brains [8]. This may be one reason why Lewy bodies are not found in the brains of rodent models of α-synucleinopathies whose life spans are much shorter when compared to that of humans [7]. Thus, it is likely that Lewy bodies are important for investigating the late pathogenesis of PD (Figure 1).

Bottom Line: In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies.However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules.Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies.

View Article: PubMed Central - PubMed

Affiliation: Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan. akio.sekigawa@zeiss.com.

ABSTRACT
Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders.

Show MeSH
Related in: MedlinePlus