The regulated release of proteins depends on their inclusion within large dense-core vesicles (LDCVs) capable of regulated exocytosis. LDCVs form at the trans-Golgi network (TGN), but the mechanism for protein sorting to this regulated secretory pathway (RSP) and the cytosolic machinery involved in this process have remained poorly understood. Using an RNA interference screen in Drosophila melanogaster S2 cells, we now identify a small number of genes, including several subunits of the heterotetrameric adaptor protein AP-3, which are required for sorting to the RSP. In mammalian neuroendocrine cells, loss of AP-3 dysregulates exocytosis due to a primary defect in LDCV formation. Previous work implicated AP-3 in the endocytic pathway, but we find that AP-3 promotes sorting to the RSP within the biosynthetic pathway at the level of the TGN. Although vesicles with a dense core still form in the absence of AP-3, they contain substantially less synaptotagmin 1, indicating that AP-3 concentrates the proteins required for regulated exocytosis.

Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD), a predominantly behavioral disease, and amyotrophic lateral sclerosis (ALS), a disease of motor neurons. The primary objectives of this review are to highlight the clinical heterogeneity associated with C9ORF72 pathogenic expansion and identify potential molecular mechanisms underlying selective vulnerability of distinct neural populations. The proposed mechanisms by which C9ORF72 expansion causes behavioral and motor neuron disease highlight the emerging role of impaired RNA and protein homeostasis in a spectrum of neurodegeneration and strengthen the biological connection between FTD and ALS.

Microglia, the brain-resident myeloid cells, are strongly implicated in Alzheimer's disease (AD) pathogenesis by human genetics. However, the mechanisms by which microglial gene expression is regulated in a region-specific manner over the course of normal aging and in neurodegenerative disease are only beginning to be deciphered. Herein, we used a specific marker of microglia (TMEM119) and a cell-type expression profiling tool (CellMapper) to identify a human microglial gene expression module. Surprisingly, we found that microglial module genes are robustly expressed in several healthy human brain regions known to be vulnerable in AD, in addition to other regions affected only later in disease or spared in AD. Surveying the microglial gene set for differential expression over the lifespan in mouse models of AD and a related tauopathy revealed that the majority of microglial module genes were significantly upregulated in cortex and hippocampus as a function of age and transgene status. Extending these results, we also observed significant upregulation of microglial module genes in several AD-affected brain regions in addition to other regions using postmortem brain tissue from human AD samples. In pathologically confirmed AD cases, we found preliminary evidence that microglial genes may be dysregulated in a sex-specific manner. Finally, we identified specific and significant overlap between the described microglial gene set-identified by unbiased co-expression analysis-and genes known to impart risk for AD. Our findings suggest that microglial genes show enriched expression in AD-vulnerable brain regions, are upregulated during aging and neurodegeneration in mice, and are upregulated in pathologically affected brain regions in AD. Taken together, our data-driven findings from multiple publicly accessible datasets reemphasize the importance of microglial gene expression alterations in AD and, more importantly, suggest that regional and sex-specific variation in microglial gene expression may be implicated in risk for and progression of neurodegenerative disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular transport of TREM2. We find that most pathogenic TREM2 mutant proteins fail to undergo normal maturation in the Golgi complex and show markedly reduced cell-surface expression. Prior research has suggested that two such mutants are retained in the endoplasmic reticulum (ER), but we find, using a cell-free coat protein complex II (COPII) vesicle budding reaction, that mutant TREM2 is exported efficiently from the ER. In addition, mutant TREM2 becomes sensitive to cleavage by endoglycosidase D under conditions that inhibit recycling to the ER, indicating that it normally reaches a post-ER compartment. Maturation-defective TREM2 mutants are also efficiently bound by a lectin that recognizes O-glycans added in the ER-Golgi intermediate compartment (ERGIC) and cis-Golgi cisterna. Finally, mutant TREM2 accumulates in the ERGIC in cells depleted of COPI. These results indicate that efficient ER export is not sufficient to enable normal cell-surface expression of TREM2. Moreover, our findings suggest that the ERGIC may play an underappreciated role as a quality-control center for mutant and/or malformed membrane proteins.

Microglia play a critical but poorly understood role in promoting white-matter homeostasis. In this review, we leverage advances in human genetics and mouse models of leukodystrophies to delineate our current knowledge and identify outstanding questions regarding the impact of microglia on central nervous system white matter. We first focus on the role of pathogenic mutations in genes, such as TREM2, TYROBP, and CSF1R, that cause leukodystrophies in which the primary deficit is thought to originate in microglia. We next discuss recent advances in disorders such as adrenoleukodystrophy and Krabbe disease, in which microglia play an increasingly recognized role. We conclude by reviewing the roles of GRN and related genes, such as TMEM106B, PSAP, and SORT1, that affect microglial biology and associate with several types of disease, including multiple leukodystrophies as well as forms of frontotemporal dementia (FTD) presenting with white-matter abnormalities. Taken together, mouse and human data support the notion that loss of microglia-facilitated white-matter homeostasis plays an important role in the development of leukodystrophies and suggest novel mechanisms contributing to FTD.

Purpose of review

In this review we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3).

Recent findings

Over the past five years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies.

Summary

Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system and neuroinflammation, and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

Purpose of review

Over the last year, research into the immunological and inflammatory signatures of frontotemporal lobar degeneration (FTLD) has accelerated greatly. Herein, we highlight recently proposed roles of brain-resident microglia as well as peripheral myeloid cells in frontotemporal dementia (FTD)-spectrum disorders.

Recent findings

Recent unbiased genetic, transcriptomic, and proteomic surveys using human data confirm significantly altered immune-function genes as well as transcript and protein modules associated with inflammatory and immune function. Beyond human studies, novel animal models indicate important roles for both microglia and monocytes, and central involvement of genes such as Trem2, Apoe, and Tbk1.

Summary

The importance of neuroinflammatory activity in FTD pathophysiology is unambiguous, but whether this activity is primarily beneficial or detrimental remains unclear, with variable results reported for distinct disease paradigms. Going forward, it will be crucial to determine which types of microglial and peripheral myeloid responses are favorable, in response to which specific proteinopathies, and at which point in disease course.

Early-onset Alzheimer's disease (EOAD) is a rare but particularly devastating form of AD. Though notable for its high degree of clinical heterogeneity, EOAD is defined by the same neuropathological hallmarks underlying the more common, late-onset form of AD. In this review, we describe the various clinical syndromes associated with EOAD, including the typical amnestic phenotype as well as atypical variants affecting visuospatial, language, executive, behavioral, and motor functions. We go on to highlight advances in fluid biomarker research and describe how molecular, structural, and functional neuroimaging can be used not only to improve EOAD diagnostic acumen but also enhance our understanding of fundamental pathobiological changes occurring years (and even decades) before the onset of symptoms. In addition, we discuss genetic variation underlying EOAD, including pathogenic variants responsible for the well-known mendelian forms of EOAD as well as variants that may increase risk for the much more common forms of EOAD that are either considered to be sporadic or lack a clear autosomal-dominant inheritance pattern. Intriguingly, specific pathogenic variants in PRNP and MAPT-genes which are more commonly associated with other neurodegenerative diseases-may provide unexpectedly important insights into the formation of AD tau pathology. Genetic analysis of the atypical clinical syndromes associated with EOAD will continue to be challenging given their rarity, but integration of fluid biomarker data, multimodal imaging, and various 'omics techniques and their application to the study of large, multicenter cohorts will enable future discoveries of fundamental mechanisms underlying the development of EOAD and its varied clinical presentations.

Alpha-synuclein (α-syn), a major component of Lewy bodies found in Parkinson's disease (PD) patients, has been found exported outside of cells and may mediate its toxicity via cell-to-cell transmission. Here, we reconstituted soluble, monomeric α-syn secretion by the expression of DnaJ homolog subfamily C member 5 (DNAJC5) in HEK293T cells. DNAJC5 undergoes palmitoylation and anchors on the membrane. Palmitoylation is essential for DNAJC5-induced α-syn secretion, and the secretion is not limited by substrate size or unfolding. Cytosolic α-syn is actively translocated and sequestered in an endosomal membrane compartment in a DNAJC5-dependent manner. Reduction of α-syn secretion caused by a palmitoylation-deficient mutation in DNAJC5 can be reversed by a membrane-targeting peptide fusion-induced oligomerization of DNAJC5. The secretion of endogenous α-syn mediated by DNAJC5 is also found in a human neuroblastoma cell line, SH-SY5Y, differentiated into neurons in the presence of retinoic acid, and in human-induced pluripotent stem cell-derived midbrain dopamine neurons. We propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.

Recent advances in transcriptomics research have uncovered heightened interferon (IFN) responses in neurodegenerative diseases including Alzheimer's disease, primary tauopathy, Parkinson's disease, TDP-43 proteinopathy, and related mouse models. Augmented IFN signaling is now relatively well established for microglia in these contexts, but emerging work has highlighted a novel role for IFN-responsive T cells in the brain and peripheral blood in some types of neurodegeneration. These findings complement a body of literature implicating dysregulated IFN signaling in neuropsychiatric disorders including major depression and post-traumatic stress disorder. In this review, we will characterize and integrate advances in our understanding of IFN responses in neurodegenerative and neuropsychiatric disease, discuss how sex and ancestry modulate the IFN response, and examine potential mechanistic explanations for the upregulation of antiviral-like IFN signaling pathways in these seemingly non-viral neurological and psychiatric disorders.