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A Mutual Nexus Between Epilepsy and α-Synuclein: A Puzzle Pathway

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Abstract

Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.

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Data Availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Abbreviations

α-Syn:

Alpha-synuclein

PD:

Parkinson’s disease

SNARE:

N-Ethylmaleimide-sensitive factor attachment protein receptor

CNS:

Central nervous system

GABA:

Gamma-aminobutyric acid

AEDs:

Anti-epileptic drugs

NMDA:

N-Methyl-D-aspartate receptors

NFTs:

Neurofibrillary tangles

Aβ:

Amyloid-β

GSK3β:

Glycogen synthase kinase-3 beta

MAPs:

Microtubule-associated proteins

PTZ:

Pentylenetetrazole

CSF:

Cerebrospinal fluid

TLE:

Temporal lobe epilepsy

ApoE4:

Apolipoprotein E4

ER:

Endoplasmic reticulum

ROS:

Reactive oxygen species

MTLE:

Mesial temporal lobe epilepsy

SE:

Status epileptics

KA:

Kainic acid

SOD2:

Superoxide dismutase 2

BBB:

Blood-brain barrier

NF-κB:

Nuclear factor kappa B

MAPK:

Mitogen-activated protein kinase

TGF-β1:

Transforming growth factor beta

NO:

Nitric oxide

LPS:

Lipopolysaccharide

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tyrosine kinase receptor B

NPY:

Neuroprotective neuropeptide Y

PGN:

Progranulin

SNARE:

N-Ethylmaleimide-sensitive fusion attachment protein receptors

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  1. Naif H. Ali and Hayder M. Al-kuraishy contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia

    Naif H. Ali

  2. Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, M.B.Ch.B, FRCP, P.O. Box 14132, Baghdad, Iraq

    Hayder M. Al-kuraishy

  3. Jabir Ibn Hayyan Medical University, Al-Ameer Qu, P.O. Box 13, Kufa, Najaf, Iraq

    Ali I. Al-Gareeb

  4. Clinical Neurosciences Department, College of Medicine, King Faisal University, Hofuf, Saudi Arabia

    Saud A. Alnaaim

  5. Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt

    Helal F. Hetta

  6. Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, 51744, Egypt

    Hebatallah M. Saad

  7. Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt

    Gaber El-Saber Batiha

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NHA, HMA-K, and AIA conceptualized the manuscript; wrote, edited, and reviewed the main text; and approved the final edition of the manuscript. SAA, HFH, HMS, and GE-SB prepared the figures and wrote, corrected, amended, and approved the final edition of the manuscript.

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Ali, N.H., Al-kuraishy, H.M., Al-Gareeb, A.I. et al. A Mutual Nexus Between Epilepsy and α-Synuclein: A Puzzle Pathway. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04204-6

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