Human and rat brain lipofuscin proteome

Abstract

The accumulation of an autofluorescent pigment called lipofuscin in neurons is an invariable hallmark of brain aging. So far, this material has been considered to be waste material without particular relevance for cellular pathology. However, two lines of evidence argue that lipofuscin may play a yet unidentified role for pathological cellular functions: (i) Genetic forms of premature accumulation of similar autofluorescent material in neuronal ceroid lipofuscinosis indicate a direct disease-associated link to lipofuscin; (ii) Retinal pigment epithelium cell lipofuscin is mechanistically linked to age-associated macular degeneration. Here, we purified autofluorescent material from the temporal and hippocampal cortices of three different human individuals by a two-step ultracentrifugation on sucrose gradients. For human brain lipofuscin, we could identify a common set of 49 (among > 200 total) proteins that are mainly derived from mitochondria, cytoskeleton, and cell membrane. This brain lipofuscin proteome was validated in an interspecies comparison with whole brain rat lipofuscin (total > 300 proteins), purified by the same procedure, yielding an overlap of 32 proteins (64%) between lipofuscins of both species. Our study is the first to characterize human and rat brain lipofuscin and identifies high homology, pointing to common cellular pathomechanisms of age-associated lipofuscin accumulation despite the huge (40-fold) difference in the lifespan of these species. Our identification of these distinct proteins will now allow research in disturbed molecular pathways during age-associated dysfunctional lysosomal degradation.

Aging-Induced Proteostatic Changes in the Rat Hippocampus Identify ARP3, NEB2 and BRAG2 as a Molecular Circuitry for Cognitive Impairment

“…In addition, the work of David and co-workers shared the detection of up-regulated myosins with the present study [20]. The study conducted by Reis-Rodrigues et al reported findings – similar to our results for rat hippocampi – of elevated levels of aggregated tubulin and mitochondrial ATP synthase subunit alpha in aged worms [19], with the latter protein component having been recognized as a common denominator in the aging-pigment lipofuscin [96,97]. The increase of 60S ribosomal protein in the insoluble fraction of the aged animals, observed in the nematode studies [19,20], however, opposes our findings of a decrease in aged rat brain aggregome.…”

Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues

“…Such accumulation possibly reflects the inability of nonproliferating cells to dispose of lipofuscin by cellular division, a process that naturally results in dilution of lipofuscin [32]. Lipofuscin accumulation in aged tissues and age- related pathologies is considered a progressive phenomenon, probably as a consequence of the decline of the cellular clearance systems of misfolded (lipo)proteins and possibly other ‘aberrant’ metabolites [16, 33, 34]. We observed the lipofuscin granules in cells shortly after they became senescent.…”

Effects of Melatonin on Nervous System Aging: Neurogenesis and Neurodegeneration

“…Many deposits accumulate in the nervous system because of the increase in damaged macromolecules and the impairment of degradation mechanisms. In contrast with the assumed nature of lipofuscin as age-associated waste deposits with lysosomal origin (14), the appearance of oxidatively cross-linked proteins in lipofuscin deposits (15) shows that this accumulation is a significant adaptation process (16). Intracellular F-actin rich hirano bodies, which are found most commonly in aged hippocampal CA1, peripheral neuronal axons, and glia, contain a C-terminal fragment of amyloid-precursor protein intracellular domain (AICD).…”