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Role of Liver Growth Factor (LGF) in Parkinson’s Disease: Molecular Insights and Therapeutic Opportunities

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Abstract

Parkinson’s disease is the most common neurodegenerative movement disorder with unclear etiology and only symptomatic treatment to date. Toward the development of novel disease-modifying agents, neurotrophic factors represent a reasonable and promising therapeutic approach. However, despite the robust preclinical evidence, clinical trials using glial-derived neurotrophic factor (GDNF) and neurturin have been unsuccessful. In this direction, the therapeutic potential of other trophic factors in PD and the elucidation of the underlying molecular mechanisms are of paramount importance. The liver growth factor (LGF) is an albumin–bilirubin complex acting as a hepatic mitogen, which also exerts regenerative effects on several extrahepatic tissues including the brain. Accumulating evidence suggests that intracerebral and peripheral administration of LGF can enhance the outgrowth of nigrostriatal dopaminergic axonal terminals; promote the survival, migration, and differentiation of neuronal stem cells; and partially protect against dopaminergic neuronal loss in the substantia nigra of PD animal models. In most studies, these effects are accompanied by improved motor behavior of the animals. Potential underlying mechanisms involve transient microglial activation, TNF-α upregulation, and activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) and of the transcription factor cyclic AMP response-element binding protein (CREB), along with anti-inflammatory and antioxidant pathways. Herein, we summarize recent preclinical evidence on the potential role of LGF in PD pathogenesis, aiming to shed more light on the underlying molecular mechanisms and reveal novel therapeutic opportunities for this debilitating disease.

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Abbreviations

LGF:

Liver growth factor

PD:

Parkinson’s disease

GDNF:

Glial-derived neurotrophic factor

BDNF:

Brain-derived neurotrophic factor

CDNF:

Cerebral dopamine neurotrophic factor

ERK 1/2:

Extracellular signal-regulated kinases 1/2

CREB:

Cyclic AMP response-element binding protein

6-OHDA:

6-Hydroxy-dopamine

SVZ:

Subventricular zone

DG:

Dentate gyrus

TGF-α:

Tumor growth factor-α

APOE:

Apolipoprotein E

NSCs:

Neuronal stem cells

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Acknowledgments

Y.N.P. would like to acknowledge Monash University Malaysia for supporting with HDR Scholarship.

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This research has not received any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Efthalia Angelopoulou & Christina Piperi

  2. Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia

    Yam Nath Paudel

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  1. Efthalia Angelopoulou
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  2. Yam Nath Paudel
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  3. Christina Piperi
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E.A. carried out the literature review, conceptualized, and prepared the initial draft. Y.N.P. edited and contributed in the final manuscript. C.P. provided critical inputs, edited, and contributed to the final version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Christina Piperi.

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Angelopoulou, E., Paudel, Y.N. & Piperi, C. Role of Liver Growth Factor (LGF) in Parkinson’s Disease: Molecular Insights and Therapeutic Opportunities. Mol Neurobiol 58, 3031–3042 (2021). https://doi.org/10.1007/s12035-021-02326-9

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