This new Japanese paper makes the connection between ATP production reduction and alpha-synuclein accumulation in PD.

Review

Front Mol Neurosci

. 2025 Jan 22:17:1507033.

doi: 10.3389/fnmol.2024.1507033. eCollection 2024.

Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and α-synuclein pathology

Hirohisa Watanabe ¹, Sayuri Shima ¹, Kazuya Kawabata ¹, Yasuaki Mizutani ¹, Akihiro Ueda ^{1 2}, Mizuki Ito ^{1 3}

Affiliations Expand

• PMID: 39911281

PMCID: PMC11794324 DOI: 10.3389/fnmol.2024.1507033

Abstract

Parkinson's disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in the pentose phosphate pathway and purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple brain functions, require significant energy due to their dense synaptic activity and long-range connections. Deficits in ATP production in PD can severely impair these hubs. The energy imbalance also affects subcortical regions, including the massive axonal arbors in the striatum of substantia nigra pars compacta neurons, due to their high metabolic demand. This ATP decline may result in α-synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown and accelerated neurodegeneration. We propose an "ATP Supply-Demand Mismatch Model" to help explain the pathogenesis of PD. This model emphasizes how ATP deficits drive pathological protein aggregation, impaired autophagy, and the degeneration of key brain networks, contributing to both motor and non-motor symptoms.