Recent insights into the molecular genetics of dementia

Abstract

Our understanding of the molecular genetic basis of two common neurodegenerative dementias, Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), has greatly advanced in recent years. Progranulin mutations were identified as a major cause of FTLD and a potential susceptibility factor for other forms of dementia. In addition, through copy-number analyses of previously identified disease genes and the study of microRNA regulation in dementia, new evidence emerged to support the view that subtle variability in the expression of known disease proteins could increase the risk for sporadic forms of dementia. Finally, in late-onset AD populations, the first genome-wide association studies were performed and novel potential AD susceptibility genes reported. These exciting findings provide novel insights into the disease mechanisms underlying dementia and hold promise for the development of potential treatments.

Figure 1. The amyloid cascade hypothesis

Autosomal dominant familial forms of Alzheimer’s disease (AD) mainly result from mutations in PSEN1 and to a smaller extent from mutations in PSEN2 and APP, including APP duplications. PSEN mutations lead to aberrant γ-secretase cleavage of APP resulting in an overproduction of the more fibrillogenic Aβ42 and an increased Aβ42/Aβ40 ratio. All missense mutations in APP are located at or near the three proteolytic cleavage sites of APP and depending on their location result in (i) increased production of Aβ40 and Aβ42, (ii) increased Aβ42/Aβ40 ratio, or (ii) enhanced fibrillogenic potential of mutant Aβ, accompanied by vascular tropism responsible for cerebral amyloid angiopathy (CAA). The essence of the amyloid cascade is that the increased production or decreased clearance of Aβ peptides result in the aggregation and accumulation of Aβ, which in a yet uncertain pathogenic form, triggers a number of downstream deleterious events, finally leading to neuronal death. Recently described APP duplications in AD patients also fit this model. Although it has not been finally demonstrated, it is likely that APP duplication leads to enhanced Aβ expression, which is phenotypically associated with AD and CAA in patients. Finally, this model suggests that in sporadic forms of AD slight increases in APP expression, mediated either by genetic variants in the promoter or 3′ untranslated regions of APP or by micro RNA changes, could constitute risk factors for late-onset AD.

Figure 2. Spectrum of GRN mutations in dementia

Schematic representation of the genomic structure of progranulin (GRN) and the mRNA encoding the GRN protein. The dark blue numbered boxes in the genomic structure indicate non-coding exon 1 and coding exons 2-13. The light blue lettered boxes in the GRN protein refer to the individual granulin domains. Mutations in GRN were recently reported as a novel cause of dementia. Loss-of-function mutations in GRN result in frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-U). A total of 66 different loss-of-function mutations scattered over all GRN exons except exon 13, have been reported. These mutations are indicated with vertical black lines on the GRN exons and listed above the exons with their cDNA numbering relative to the largest GRN transcript (GenBank accession number NM_002087.2). One complete and two partial GRN deletions have also been identified as indicated with horizontal black lines above the GRN genomic structure. An additional 39 patient specific mutations with unknown pathogenic significance were identified in neurodegenerative disease patients. These include 28 missense mutations, 10 silent mutations and one nonsense mutations in GRN exon 13. These mutations are indicated with vertical lines on the GRN protein relative to the individual granulin domains and listed below the GRN protein with the protein numbering relative to GenPept accession number NP_002078.1. Each of the mutations is color coded to indicate that the mutations were identified in patients with a clinical diagnosis of FTLD (black), FTLD and ALS (orange), ALS (yellow), AD (red), AD and FTLD (green) or AD and PD (purple). Missense mutations affecting conserved cysteine residues within the granulin peptides are indicated with a hash symbol.