Nerve pathology is prevented by linker proteins in mouse models for -related muscular dystrophy.

-related muscular dystrophy (LAMA2 MD or MDC1A) is a devastating congenital muscular dystrophy that is caused by mutations in the gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by an early-onset, severe muscular dystrophy that ultimately leads to death by respiratory insufficiency.

JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice.

Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments.

Mesoangioblast delivery of miniagrin ameliorates murine model of merosin-deficient congenital muscular dystrophy type 1A.

Background: Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. MDC1A has no available treatment so far, although preclinical studies showed amelioration of the disease by the overexpression of miniagrin (MAG). MAG reconnects orphan laminin-211 receptors to other laminin isoforms available in the extracellular matrix of MDC1A mice.

Jab1 regulates Schwann cell proliferation and axonal sorting through p27.

Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211- and, possibly, neuregulin 1 (Nrg1)-derived signals.

Urokinase plasminogen receptor and the fibrinolytic complex play a role in nerve repair after nerve crush in mice, and in human neuropathies.

Remodeling of extracellular matrix (ECM) is a critical step in peripheral nerve regeneration. In fact, in human neuropathies, endoneurial ECM enriched in fibrin and vitronectin associates with poor regeneration and worse clinical prognosis. Accordingly in animal models, modification of the fibrinolytic complex activity has profound effects on nerve regeneration: high fibrinolytic activity and low levels of fibrin correlate with better nerve regeneration.

Vimentin regulates peripheral nerve myelination.

Myelination is a complex process that requires coordinated Schwann cell-axon interactions during development and regeneration. Positive and negative regulators of myelination have been recently described, and can belong either to Schwann cells or neurons. Vimentin is a fibrous component present in both Schwann cell and neuron cytoskeleton, the expression of which is timely and spatially regulated during development and regeneration.

Over-expression of amyloid precursor protein in HEK cells alters p53 conformational state and protects against doxorubicin.

Here we show that human embryonic kidney (HEK) cells stably transfected with amyloid precursor protein (HEK-APP), expressed a conformational mutant-like and transcriptionally inactive p53 isoform, and turned out to be less sensitive to the cytotoxin doxorubicin in comparison with untransfected cells. Treatment of HEK-APP cells with gamma- and beta-secretase inhibitors prevented generation of unfolded, mutant-like p53 isoform and made the cells vulnerable to doxorubicin as untransfected cells. Changes in p53 conformational state and reduced sensitivity to doxorubicin were also found in untransfected HEK cells after exposure to nanomolar concentrations of beta-amyloid (Abeta) and these effects were antagonized by vitamin E.

Role of acetylcholinesterase inhibitors in pharmacological regulation of amyloid precursor protein processing.

The triggering events leading to the selective neurodegeneration observed in Alzheimer brains are not yet completely understood. They thus create a great challenge for the definition of a resolutive treatment for the causes and symptoms of Alzheimer's Disease (AD). Since the current therapeutic option for AD patients is the use of acetylcholinesterase inhibitors (AChEIs), several authors have examined whether these drugs can also affect the expression and metabolism of the amyloid precursor protein (AbetaPP).

Role of acetylcholinesterase inhibitors in the regulation of amyloid beta precursor protein (AbetaPP) metabolism.

The events that lead to neurodegeneration in Alzheimer's brains are largely unknown and this fact creates a great challenge for the definition of treatments that may be resolutive for Alzheimer's disease (AD). The current therapeutic option for AD patients is the use of acetylcholinesterase inhibitors (AChEIs), which gives a symptomatic relief to some of the clinical manifestations of the disease. In addition, several authors investigated whether these drugs can also affect one of the major pathogenetic pathway postulated for the disease, that is the expression and metabolism of the amyloid precursor protein (AbetaPP).

Acetylcholinesterase inhibitors: novel activities of old molecules.

The therapeutic approach for improving the cognitive function in patients with Alzheimer's disease (AD) is mainly based on the potentiation of central cholinergic activity and is achieved clinically by the use of acetylcholinesterase (AChE) inhibitors such as tacrine, donepezil, rivastigmine, galantamine and other drugs currently in clinical trials. These are, by their pharmacology, only symptomatic drugs yet recently these molecules have shown some potential also in the modulation of amyloid precursor protein (APP) processing. We explore in this review the experimental evidence that suggests a role for AChEIs in APP processing and point to multiple complex mechanisms involving either a cholinergic agonist effect, coupled to multiple signal transduction pathways, or post-transcriptional effects that modulate the expression of cellular APP.

Differential involvement of protein kinase C alpha and epsilon in the regulated secretion of soluble amyloid precursor protein.

We investigated the differential role of protein kinase C (PKC) isoforms in the regulated proteolytic release of soluble amyloid precursor protein (sAPPalpha) in SH-SY5Y neuroblastoma cells. We used cells stably transfected with cDNAs encoding either PKCalpha or PKCepsilon in the antisense orientation, producing a reduction of the expression of PKCalpha and PKCepsilon, respectively. Reduced expression of PKCalpha and/or PKCepsilon did not modify the response of the kinase to phorbol ester stimulation, demonstrating translocation of the respective isoforms from the cytosolic fraction to specific intracellular compartments with an interesting differential localization of PKCalpha to the plasma membrane and PKCepsilon to Golgi-like structures.

Familial migraine with aura: association study with 5-HT1B/1D, 5-HT2C, and hSERT polymorphisms.

Background: The serotonergic system has a significant role in the pathophysiology and pharmacology of migraine.

Objective: To study the association between the occurrence of migraine with aura and 5-HT(1B/1D) and 5-HT(2C) receptor gene and the human serotonin transporter (hSERT) gene polymorphisms in 18 unrelated families with multiple affected members.

Method: Two polymorphisms in the 5-HT(1B/1D) receptor gene and one polymorphism in the 5-HT(2C) receptor gene were studied by restriction fragment length polymorphism analysis.