Dynamic functional connectivity variability may explain hypoxia-induced cognitive impairment at high-altitude.

Intracellular accumulation of α-synuclein (αS) aggregates is a common pathological hallmark of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy [, ]. In the diseased brains, αS undergoes structural changes and forms β-sheet-rich amyloid filaments [, ]. Progressive distribution of αS pathology correlates with the clinical stages of sporadic PD [], suggesting that αS propagation contributes to disease progression. Therefore, targeting the propagation of pathological αS has emerged as a promising therapeutic strategy. However, no disease-modifying therapies have been developed to date. Experimental evidence supporting the prion-like propagation of αS has been obtained in vivo. Intracerebral injection of preformed αS fibrils (PFFs) into nontransgenic animals induces conversion of endogenous αS into insoluble aggregates and promotes time-dependent propagation of αS pathology from the injection site to anatomically connected regions [, , , , ]. Previously, we reported that porphyrin compounds inhibit the aggregation of αS, tau, and Aβ in vitro [, , ]. However, their high molecular weight limits permeability across the BBB. Recently, a novel strategy employing porphyrins conjugated to BBB-permeable peptides has been proposed to enhance brain delivery, particularly as a therapeutic approach against viral infection [, ]. An alternative strategy to overcome this limitation is to enhance endogenous production of porphyrin-related molecules within the brain. All cells, including neurons, can produce heme, a porphyrin derivative, through the heme biosynthetic pathway. This pathway comprises eight enzymatic reactions spanning the mitochondria and cytoplasm. It is initiated in the mitochondria by the condensation of glycine and succinyl-CoA to generate 5-ALA by ALA synthase 5-ALA is then exported to the cytoplasm, where four consecutive reactions produce coproporphyrinogen III. This intermediate is transported back into the mitochondria and further processed by coproporphyrinogen oxidase and protoporphyrinogen oxidase to generate protoporphyrin IX (PPIX). In the final step, ferrochelatase catalyzes the incorporation of ferrous ion into PPIX, yielding heme. Overall, one molecule of heme is synthesized from eight molecules of 5-ALA and one ferrous ion [].