Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.

Proteome maintenance in contracting skeletal and cardiac muscles depends on the chaperone-regulating protein BAG3. Reduced BAG3 activity leads to muscle weakness and heart failure in animal models and patients. BAG3 and its chaperone partners recognize mechanically damaged muscle proteins and initiate their disposal through chaperone-assisted selective autophagy (CASA).

Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles.

Background: The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death.

Microglial derived extracellular vesicles activate autophagy and mediate multi-target signaling to maintain cellular homeostasis.

Microglia, the immunocompetent cells of the central nervous system (CNS), play an important role in maintaining cellular homeostasis in the CNS. These cells secrete immunomodulatory factors including nanovesicles and participate in the removal of cellular debris by phagocytosis or autophagy. Accumulating evidence indicates that specifically the cellular exchange of small extracellular vesicles (EVs), participates in physiology and disease through intercellular communication.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI.

Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia.

Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies.

HSPB1 (heat shock protein family B [small] member 1) is a ubiquitously expressed molecular chaperone. Most mutations in HSPB1 cause axonal Charcot-Marie-Tooth neuropathy and/or distal hereditary motor neuropathy. In this study we show that mutations in HSPB1 lead to impairment of macroautophagic/autophagic flux.

Clinical variability and onset age modifiers in an extended Belgian GRN founder family.

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree.

Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease.

The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor.

Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL).

Objective: To characterize the clinical and MRI features of 2 families with adult-onset dominant leukoencephalopathy and strokes and identify the underlying genetic cause.

Methods: We applied MRI pattern recognition, whole-exome sequencing, and neuropathology.

Results: Based on brain imaging, 13 family members of 40 years or older from 2 families were diagnosed with the disease; in 11 family members of the same age, MRI was normal.

Shwachman-Diamond syndrome presenting with early ichthyosis, associated dermal and epidermal intracellular lipid droplets, hypoglycemia, and later distinctive clinical SDS phenotype.

Shwachman-Diamond syndrome (SDS) is a recessive ribosomopathy, characterized by bone marrow failure and exocrine pancreatic insufficiency (ePI) often associated with neurodevelopmental and skeletal abnormalities. The aim of this report is to describe a SDS patient with early ichthyosis associated with dermal and epidermal intracellular lipid droplets (iLDs), hypoglycemia and later a distinctive clinical SDS phenotype. At 3 months of age, she had ichthyosis, growth retardation, and failure to thrive.

Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes.

Background: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1β and IL-18. However, their role in response to injury in the nervous system is less understood.

Frontotemporal lobar degeneration: current concepts in the light of recent advances.

Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS).

Genetics and pathology of alpha-secretase site AbetaPP mutations in the understanding of Alzheimer's disease.

Development of therapeutics begins with delineating the precise disease pathology along with a reasonable understanding of the sequence of events responsible for the development of disease, or disease pathogenesis. For Alzheimer's disease (AD), the classical pathology is now known for quite some time; however, the disease pathogenesis has eluded our understanding for a complete century. This review, in addition to providing a brief overview of all primary events, will highlight those aspects of AD genetics and novel pathological descriptions linked to unique mutations within AbetaPP that have led to our better understanding of the pathogenesis of AD.