Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

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Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Biology Open ◽

10.1242/bio.054338 ◽

2020 ◽

Vol 9 (10) ◽

pp. bio054338

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network ◽

Main Component

ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2018.01.006 ◽

2018 ◽

Vol 88 ◽

pp. 70-82 ◽

Cited By ~ 13

Author(s):

Abeje Ambaw ◽

Lingxing Zheng ◽

Mitali A. Tambe ◽

Katherine E. Strathearn ◽

Glen Acosta ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Alpha Synuclein ◽

Alpha Synuclein Aggregation

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Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

10.1101/2019.12.20.884643 ◽

2019 ◽

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Faculty Opinions recommendation of Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008343.104560 ◽

2002 ◽

Author(s):

John Hardy

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transgenic Mice ◽

Neurodegenerative Disease ◽

Alpha Synuclein ◽

Alpha Synuclein Aggregation ◽

Familial Parkinson’S Disease

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Alpha Synuclein Aggregation in a Neurotoxic Model of Parkinson's Disease

10.21236/ada393984 ◽

2000 ◽

Author(s):

Neil W. Kowall

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Alpha Synuclein Aggregation

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TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713969114 ◽

2017 ◽

Vol 114 (40) ◽

pp. 10773-10778 ◽

Cited By ~ 40

Author(s):

Seong Su Kang ◽

Zhentao Zhang ◽

Xia Liu ◽

Fredric P. Manfredsson ◽

Matthew J. Benskey ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Death ◽

Kinase Domain ◽

Alpha Synuclein ◽

Mao B ◽

Protein Levels ◽

Trkb Receptors ◽

Alpha Synuclein Aggregation ◽

Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

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Neuroprotective Effects of Gagam-Sipjeondaebo-Tang, a Novel Herbal Formula, against MPTP-Induced Parkinsonian Mice and MPP+-Induced Cell Death in SH-SY5Y Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/2420809 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jade Heejae Ko ◽

Ju-Hee Lee ◽

Bobin Choi ◽

Ju-Yeon Park ◽

Young-Won Kwon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Mitochondrial Dysfunction ◽

Apoptotic Cell ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Motor Dysfunction ◽

Herbal Formula ◽

Neuroprotective Effects

Parkinson’s disease is a neurodegenerative disease characterized by progressive cell death of dopaminergic neuron and following neurological disorders. Gagam-Sipjeondaebo-Tang (GST) is a novel herbal formula made of twelve medicinal herbs derived from Sipjeondaebo-Tang, which has been broadly used in a traditional herbal medicine. In the present study, we investigated the effects of GST against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor abnormalities in mice and 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in SH-SY5Y cell. First, we found that GST alleviated motor dysfunction induced by MPTP, and the result showed dopaminergic neurons recovery in substantia nigra. In the cell experiment, pretreatment with GST increased the cell viability and attenuated apoptotic cell death in MPP+-treated SH-SY5Y cells. GST also inhibited reactive oxygen species production and restored the mitochondrial membrane potential loss, which were induced by MPP+. Furthermore, GST extract significantly activated ERK and Akt, cell survival-related proteins, in SH-SY5Y cells. The effect of GST preventing mitochondrial dysfunction was antagonized by pretreatment of PD98059 and LY294002, selective inhibitors of ERK and Akt, respectively. Taken together, GST alleviated abnormal motor functions and recovered neuronal cell death, mitochondrial dysfunction, possibly via ERK and Akt activation. Therefore, we suggest that GST may be a candidate for the treatment and prevention of Parkinson’s disease.

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