Peripheral immune cell response to stimulation stratifies Parkinson's disease progression from prodromal to clinical stages.

The motor stage of idiopathic Parkinson's disease (iPD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD). Here, we show that multiple stages of iPD, including the pre-motor prodromal stage, can be stratified according to the inflammatory and immunometabolic responses to stimulation of peripheral blood mononuclear cells . We identified increased stimulation-dependent secretion of TNF, IL-1β, and IL-8 in monocytes from RBD patients and showed diminished proinflammatory cytokine secretion in monocytes and T cells in early and moderate stages of PD.

The mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice.

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear.

Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines.

ASO-mediated knockdown of GPNMB in mutant- and -deficient peripheral myeloid cells disrupts lysosomal function and immune responses.

Background: Increases in GPNMB are detectable in FTD- cerebrospinal fluid (CSF) and post-mortem brain, and brains of aged -deficient mice. Although no upregulation of GPNMB is observed in the brains of young -deficient mice, peripheral immune cells of these mice do exhibit this increase in GPNMB. Importantly, the functional significance of GPNMB upregulation in progranulin-deficient states is currently unknown.

Investigating the Role and Regulation of GPNMB in Progranulin-deficient Macrophages.

Progranulin is a holoprotein that is critical for successful aging, and insufficient levels of progranulin are associated with increased risk for developing age-related neurodegenerative diseases like AD, PD, and FTD. Symptoms can vary widely, but a uniting feature among these different neurodegenerative diseases is prodromal peripheral immune cell phenotypes. However, there remains considerable gaps in the understanding of the function(s) of progranulin in immune cells, and recent work has identified a novel target candidate called GPNMB.

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.

Background: Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB).

Main Body: It is unclear what role GPNMB plays in the context of PGRN insufficiency and how they interact and contribute to the development or progression of NDs.

ASO-mediated knockdown or kinase inhibition of -Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages.

Genetic variation around the gene affects risk for both familial and sporadic Parkinson's disease (PD). LRRK2 levels have become an appealing target for potential PD therapeutics with LRRK2 antisense oligonucleotides (ASOs) now moving toward clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious.

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner.

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered.

Totally tubular: ASO-mediated knock-down of -Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages.

Genetic variation around the gene affects risk of both familial and sporadic Parkinson's disease (PD). LRRK2 levels have become an appealing target for potential PD-therapeutics with LRRK2 antisense oligonucleotides (ASOs) now in clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious.

APOE and immunity: Research highlights.

Introduction: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias.

Methods: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry.

Results: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.

Disease mechanisms as subtypes: Lysosomal dysfunction in the endolysosomal Parkinson's disease subtype.

Parkinson's disease (PD) remains one of the most prevalent neurodegenerative disorders. It has become increasingly recognized that PD is not one disease but a constellation of many, with distinct cellular mechanisms driving pathology and neuronal loss in each given subtype. Endolysosomal trafficking and lysosomal degradation are crucial to maintain neuronal homeostasis and vesicular trafficking.

Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system.

Introduction: Progranulin (PGRN) is a secreted glycoprotein, the expression of which is linked to several neurodegenerative diseases. Although its specific function is still unclear, several studies have linked it with lysosomal functions and immune system regulation. Here, we have explored the role of PGRN in peripheral and central immune system homeostasis by investigating the consequences of PGRN deficiency on adaptive and innate immune cell populations.

WHOPPA Enables Parallel Assessment of Leucine-Rich Repeat Kinase 2 and Glucocerebrosidase Enzymatic Activity in Parkinson's Disease Monocytes.

Both leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase) are promising targets for the treatment of Parkinson's disease (PD). Evidence suggests that both proteins are involved in biological pathways involving the lysosome. However, studies to date have largely investigated the enzymes in isolation and any relationship between LRRK2 and GCase remains unclear.

Inflammation and immune dysfunction in Parkinson disease.

Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process.

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson's.

It is becoming increasingly accepted that there is an interplay between the peripheral immune response and neuroinflammation in the pathophysiology of Parkinson's disease (PD). Mutations in the () gene are associated with familial and sporadic cases of PD but are also found in immune-related disorders, such as inflammatory bowel disease (IBD) and leprosy. Furthermore, LRRK2 has been associated with bacterial infections such as and .

Linking mitochondria to the immune response.

A gene associated with Parkinson's disease regulates mitochondrial homeostasis, thus affecting innate immunity.

LRRK2 regulation of immune-pathways and inflammatory disease.

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease but are also found in immune-related disorders such as inflammatory bowel disease, tuberculosis and leprosy. LRRK2 is highly expressed in immune cells and has been functionally linked to pathways pertinent to immune cell function, such as cytokine release, autophagy and phagocytosis. Here, we examine the current understanding of the role of LRRK2 kinase activity in pathway regulation in immune cells, drawing upon data from multiple diseases associated with LRRK2 to highlight the pleiotropic effects of LRRK2 in different cell types.

Lysosomal Dysfunction at the Centre of Parkinson's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Parkinson's disease (PD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) are insidious and incurable neurodegenerative diseases that represent a significant burden to affected individuals, caregivers, and an ageing population. Both PD and FTD/ALS are defined at post mortem by the presence of protein aggregates and the loss of specific subsets of neurons. We examine here the crucial role of lysosome dysfunction in these diseases and discuss recent evidence for converging mechanisms.

LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function.

Lysosomal dysfunction lies at the centre of the cellular mechanisms underlying Parkinson's disease although the precise underlying mechanisms remain unknown. We investigated the role of leucine-rich repeat kinase 2 (LRRK2) on lysosome biology and the autophagy pathway in primary neurons expressing the human LRRK2-G2019S or LRKK2-R1441C mutant or the human wild-type (hWT-LRRK2) genomic locus. The expression of LRRK2-G2019S or hWT-LRRK2 inhibited autophagosome production, whereas LRRK2-R1441C induced a decrease in autophagosome/lysosome fusion and increased lysosomal pH.

LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.

Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions.

Cellular processes associated with LRRK2 function and dysfunction.

Mutations in the leucine-rich repeat kinase 2 (LRRK2)-encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2-Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions.