Fig. 2

The molecular processes implicated in neurodegeneration in the neurons of a normal healthy individual (gray) and in AD (red), PD (blue), and HD (yellow) patients. The schematic neuron is divided into the soma and axonal terminal bouton. For simplicity, postsynaptic/dendritic events are not included. Misfolded proteins aggregate first into oligomers and then into higher-molecular-weight insoluble protofibrils and further aggregates [17, 37, 104]. In AD patients with mutations in APP, PSEN1, PSEN2, or APOE, the JNK pathway is activated, increasing levels of phospho-JNK in neurons. This mediates the phosphorylation of APP and FoxO-dependent autophagy [52, 63]. Moreover, the soluble Aβ oligomers activate the mTOR pathways again promoting autophagy [52]. Further phosphorylation of tau and impaired Aβ activate the IIS/Akt pathways and affect cognitive function and synaptic plasticity [38]. In PD, mutations in PINK and Parkin (related to EOPD) or α-synuclein mutations (LOPD) lead to the inhibition of α-synuclein degradation as well as accumulation of autophagic vacuoles, which result in neuronal death [16, 96]. Misfolded α-synuclein also interacts with membranes and mitochondria, causing calcium dysregulation and a reduction of mitochondrial activity. This results in mtDNA damage as well as impairments to the ubiquitin-proteasome system (UPS) and mitophagy. The significant pathological etiology of HD is the enlargement of the polyglutamine (polyQ) domain within the HTT protein’s N-terminus [110]. MLH1 (MutL homolog 1) and an SNP within a nuclear factor-κB binding site (Nf-KB) in the HTT promoter play a role in the altered onset of HD. In comparison with AD and PD, proteasome efficiency is strongly reduced in HD patients. Meanwhile, the polyQ domain of mutant HTT contributes increased toxicity by attracting and binding to other cytoplasmic and nuclear structures that contain polyglutamine (reviewed by [6]). Additionally, a major loss of brain-derived neurotrophic factor (BDNF) protein has been shown in HD and may due to the deficits in BDNF delivery and/or loss of BDNF gene transcription by mutant Htt [23, 39]