Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

Abstract

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency o5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G4A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G4A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

“…The patient had a family history of early-onset dementia and pathology examination of her brain revealed extensive Lewy body pathology (neocortical-type DLB) as well as severe Alzheimer pathology (Braak stage 6, CERAD score C) (table 2). The second APP mutation we detected, p.E599K, has been previously associated with parkinsonism (Schulte, et al, 2015) and likely constitutes a risk variant. In total, 2% of our cohort carried an APP missense mutation.…”

Ferroptosis and cell death mechanisms in Parkinson's disease

“…Ceruloplasmin (CP) enables iron export by converting Fe 2+ to Fe 3+ (Osaki et al, 1966), which is then bound to and removed by transferrin. Several rare variants of APP predispose individuals to PD (Schulte et al, 2015), and examination of several studies of familial AD indicate APP mutations are associated with parkinsonism (Edwards-Lee et al, 2005;Rosenberg et al, 2000), and LB formation (Halliday et al, 1997;Rosenberg et al, 2000). Similarly, several point mutations in the CP-encoding gene are significantly associated with PD (Hochstrasser et al, 2004), and parkinsonism (Kohno et al, 2000;Miyajima et al, 2003), indicating that CP-mediated iron homeostasis mechanisms are also likely involved in PD pathogenesis.…”

“…Evidence supporting pathological involvement of ferroptosis in humans (blue circles), and evidence suggesting pharmacological modulators of ferroptosis could be beneficial in PD (purple circles). Blue: (1) transferrin (Tf)-mutations increase susceptibility (Borie et al, 2002;Rhodes et al, 2014); (2) ceruloplasmin (CP)-mutations increase susceptibility (Rhodes et al, 2014); (3) amyloid precursor protein (APP)-mutations increase susceptibility, expression levels reduced in PD (Ayton et al, 2015b;Schulte et al, 2015); (4) reduced-glutathione-nigral depletion (Jenner et al, 1992); (5) ferrous iron (Fe(II))-nigral elevation ; Dexter et al, 1991;Dexter et al, 1989b;Good et al, 1992;Hirsch et al, 1991;Lei et al, 2012;Sofic et al, 1988); (6) lipid peroxidation-nigral elevation (Dexter et al, 1989a, Dexter et al, 1986. Purple: (1) deferiprone (DFP)-motor improvement in phase II clinical trial.…”

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing

“…In the amyloidogenic path way cleavage by β-secretase (BACE) and γ-secretase releases amyloid-β42 (Aβ42), which plays an important role in early pathological events in early-onset familial AD and sporadic age-related AD (8,10). Moreover, previous studies have shown that other age-related diseases, such as Parkinson's disease and age-related macular degeneration, are accompanied by high levels of expression of APP (11)(12)(13)(14). However, the biological activity of APP in SK is unknown.…”