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The Role of PKM2 in Multiple Signaling Pathways Related to Neurological Diseases

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Abstract

Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. It is well known that PKM2 plays a vital role in the proliferation of tumor cells. However, PKM2 can also exert its biological functions by mediating multiple signaling pathways in neurological diseases, such as Alzheimer’s disease (AD), cognitive dysfunction, ischemic stroke, post-stroke depression, cerebral small-vessel disease, hypoxic-ischemic encephalopathy, traumatic brain injury, spinal cord injury, Parkinson’s disease (PD), epilepsy, neuropathic pain, and autoimmune diseases. In these diseases, PKM2 can exert various biological functions, including regulation of glycolysis, inflammatory responses, apoptosis, proliferation of cells, oxidative stress, mitochondrial dysfunction, or pathological autoimmune responses. Moreover, the complexity of PKM2’s biological characteristics determines the diversity of its biological functions. However, the role of PKM2 is not entirely the same in different diseases or cells, which is related to its oligomerization, subcellular localization, and post-translational modifications. This article will focus on the biological characteristics of PKM2, the regulation of PKM2 expression, and the biological role of PKM2 in neurological diseases. With this review, we hope to have a better understanding of the molecular mechanisms of PKM2, which may help researchers develop therapeutic strategies in clinic.

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Abbreviations

PKM2:

Pyruvate kinase M2

AD :

Alzheimer’s disease

PD:

Parkinson’s disease

PK:

Pyruvate kinase

PEP:

Phosphoenolpyruvate

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

HIF-1α:

Hypoxia-inducible factor 1α

HRE:

Hypoxia response element

PI3K:

Phosphoinositide 3-kinase

mTOR:

Mammalian target of rapamycin

AMPK:

AMP-activated protein kinase

PTEN:

Phosphatase and tensin homolog

EGFR:

Epidermal growth factor receptor

PKC:

Protein kinase C

NF-κB:

Nuclear factor kappa enhancer binding protein

PPAR-γ:

Peroxisome proliferator-activated receptor γ

mTORC2:

Mammalian target of rapamycin complex 2

AKT:

Protein kinase B

APJ:

Angiotensin II receptor-like 1

SRSF3:

Arginine rich splicing factor 3

PTBP1:

Polypyrimidine tract binding protein 1

hnRNPA1/A2:

Heterogeneous nuclear ribonucleoprotein A1/A2

circRNA:

Circular RNAs

circSRRM4:

CircRNA serine/arginine repetitive matrix 4

miRNAs:

MicroRNAs

miR-124:

MicroRNA-124

RBM4:

RNA-binding motif 4

PHB2:

Prohibitin 2

lncRNAs:

Long non-coding RNAs

LINC00689:

LncRNA long intergenic non-protein coding RNA 689

ceRNA:

Competing endogenous RNA

circMAT2B:

Circular RNA MAT2B

Mbd2:

Methyl-CpG binding domain protein 2

PPP:

Pentose phosphate pathway

FBP:

Fructose-1,6-bisphosphate

PHD3:

Prolyl hydroxylase 3

GLUT1:

Glucose transporter 1

LDHA:

Lactate dehydrogenase A

PDK1:

Pyruvate dehydrogenase kinase 1

iNs:

Induced neurons

LDH5:

Lactate dehydrogenase isoform 5

MCTs:

Monocarboxylate transporters

NMDA:

N-methyl-D-aspartate

NMDAR:

NMDA receptor

ERK1/2:

Extracellular signal-regulated protein kinases 1 and 2

Bcl-2:

B-cell lymphoma 2

Bax:

Bcl2-associated X

CDKs:

Cyclin-dependent kinases

STAT3:

Signal transducers and activators of transcription 3

6-OHDA:

6-Hydroxydopamine

LPS:

Lipopolysaccharide

Wnt:

Wingless/integrated

GCI:

Global cerebral ischemia

5′ Tyr-tRF:

5′ TRNA fragments derived from tyrosine pre-tRNA

CCND1:

Cyclin D1

HDACs:

Histone deacetylases

MAPK:

Mitogen-activated protein kinase

SCI:

Spinal cord injury

TCF4:

T-cell factor 4

FAK:

Focal adhesion kinase

VEGF:

Vascular epithelial growth factor

VCP:

Valosin-containing protein

TLRs:

Toll-like receptors

Pyk2:

Proline-rich tyrosine kinase 2

PGC-1α:

Peroxisome proliferator-activated receptor-γ co-activator 1-α

HMGB1:

High-mobility group box 1

NLRP3:

NLR family, pyrin domain containing 3

AIM2:

Absent in melanoma 2

EIF2AK2 or PKR:

Eukaryotic translation initiation factor 2 alpha kinase 2

iNOS:

Inducible nitric oxide synthase

COX-2:

Cyclooxygenase-2

MyD88:

Myeloid differentiation factor 88

TRAF6:

TNF receptor-associated factor 6

NOX4:

NADPH oxidase 4

IFN-γ:

Interferon-γ

ROS:

Reactive oxygen species

ATF2:

Activation transcription factor 2

H3:

Histone 3

C1q:

Complement component 1q

TNF:

Tumor necrosis factor

IL:

Interleukin

C3:

Complement component 3

C3aR:

C3a receptors

RA:

Rheumatoid arthritis

Th17:

Helper T cells 17

DCs:

Dendritic cells

JNK:

C-Jun N-terminal kinase

mDCs:

Myeloid dendritic cells

RNS:

Reactive nitrogen species

NADPH:

Nicotinamide adenine dinucleotide phosphate hydride

GSH:

Reduced glutathione

Nrf2:

Nuclear factor-erythroid-2-related factor 2

GPX4:

Glutathione peroxidase 4

Gclc:

The catalyzing subunit of glutamate-cysteine ligase

Gclm:

The modifying subunit of glutamate-cysteine ligase

NQO1:

NADPH quinone oxidoreductase 1

TrxR1:

Thioredoxin reductase 1

Trx:

Thioredoxin

NAD + :

Nicotinamide adenine dinucleotide

NADH:

Reduced nicotinamide adenine dinucleotide

UPR:

Unfolded protein response

ARE:

Antioxidant response element

Drp1:

Dynamin-related protein 1

Mfn2:

Mitochondrial fusion protein 2

MMP:

Mitochondrial membrane potential

OPA1:

Optic atrophy 1

PP1:

Protein phosphatase 1

FUNDC1:

FUN14 domain-containing 1

Aβ:

Amyloid β-peptide

APH1:

Aph-1 homolog

NCT:

Nicastrin

IFITM3:

Interferon-induced transmembrane protein 3

NPSLE:

Neuropsychiatric systemic lupus erythematosus

MCI:

Mild cognitive impairment

BDNF:

Brain-derived neurotrophic factor

PSD:

Post-stroke depression

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Funding

This work was supported by the National Natural Science Foundation of China (grant number 82060218).

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  1. Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China

    Xiaoping Zhang, Yihui Lei, Hongyan Zhou, Haijun Liu & Ping Xu

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  1. Xiaoping Zhang
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All authors contributed to the study’s conception and design. The first draft of the manuscript was written by Xiaoping Zhang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Zhang, X., Lei, Y., Zhou, H. et al. The Role of PKM2 in Multiple Signaling Pathways Related to Neurological Diseases. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03901-y

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