Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson's disease

Abstract

This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia. In aging and genetic predisposition with lipid disturbance, α-synuclein's normal vesicular and synaptic role may be detrimentally shifted toward accommodating and binding such lipids. Specific neuronal glycolipid, protein, and vesicular interactions create potential pathophysiology that is amplified by astroglial and microglial immune mechanisms resulting in neurodegeneration. This perspective provides a new logic for therapeutic interventions that do not focus on protein aggregation, but rather provides a guide to the complex biology and the common sequence of events that lead to age-dependent neurodegenerative disorders.

Keywords: APOE; Apolipoprotein; Astroglia; GBA; Immune; Inflammation; Lipids; Lysosome; Microglia; Neurons; Tau; α-Synuclein.

Fig. 1

Time and glycosphingolipid dose-dependent phenotypic disease expressions. GBA1 homozygous or compound heterozygous mutations cause Gaucher disease with onset in early life. Such mutations cause major reductions in glucocerebrosidase (GCase) enzymatic activity and massive accumulation of sphingolipid substrates (glucosylceramide and glucosylsphingosine), typically leading to fatal organ failures particularly of the liver and spleen. In the case of Parkinson’s disease (PD), with or without heterozygous GBA1 mutations, disease prevalence is in late life (above age 65) and approaches 1–3% of the population. In PD, GCase activity is typically reduced by ~ 50% in the brain and blood with a moderate elevation of glycosphingolipids. Data from post-mortem human brain tissue and in mouse brain also shows that GCase activity is gradually decreased in the brain during normal aging at levels that mirrors genetic GCase haploinsufficiency. Presumably, this contributes to increased risk in all humans with age for PD

Fig. 2

Lysosomal, lipid, and cellular mechanisms leading to α-synuclein and Lewy body pathology. a Under normal conditions α-synuclein is a natively structured protein with synaptic and vesicular functions. In addition to monomeric α-synuclein, α-synuclein can exist as physiological α-synuclein multimers (tetramers). α-Synuclein is normally transported to intracellular sites, including the synapse, where it participates in synaptic release functions. b Several pathways are involved in the degradation of α-synuclein and maintenance of its steady-state levels, including the ubiquitin-proteasome system (UPS), and c endo-lysosomal pathways. Overexpression of the ubiquitin ligase, Nedd4, can rescue α-synuclein toxicity in animal models through increased degradation of α-synuclein through the endo-lysosomal pathway (see text). c GBA haploinsufficiency, or deficiencies in other lysosomal enzymes, chaperones or transport proteins, can cause dysfunction of the lysosome in Parkinson’s disease (PD) and Lewy body dementia (LBD). Increased expression or function of lysosomal enzymes including GBA and Lamp1 reduce α-synucleinopathy and can rescue midbrain dopamine neuron degeneration in α-synucleinopathy preclinical models. d Damaged mitochondria are degraded through the mitophagy pathway, which can also be disrupted in aging and in familial PD and increases autophagic lysosomal load. e As described in this review, the structural similarity of α-synuclein with apolipoproteins suggests an additional role for α-synuclein in lipid transport. An aberrant accumulation of lipids, including glycosphingolipids in aging and in PD, are associated with abnormal lipidation of α-synuclein, and eventually accumulation of α-synuclein into insoluble high molecular weight forms. Mutations in, overexpression of, and loss of function of α-synuclein, contribute to cellular toxicities and pathology, including perturbation of lipid-vesicle trafficking and axonal transport. Recent advanced microscopic evidence shows that the Lewy body is composed of a large lipid core also including cellular organelles including mitochondria, lipids and protein aggregates. ER (endoplasmic reticulum), Lys (lysosome), Mt (mitochondria), Ub (ubiquitin), Ves (vesicle)